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18.3: T Lymphocytes - Biology

18.3: T Lymphocytes - Biology


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Learning Objectives

  • Describe the process of T-cell maturation and thymic selection
  • Explain the genetic events that lead to diversity of T-cell receptors
  • Compare and contrast the various classes and subtypes of T cells in terms of activation and function
  • Explain the mechanism by which superantigens effect unregulated T-cell activation

As explained in Overview of Specific Adaptive Immunity, the antibodies involved in humoral immunity often bind pathogens and toxins before they can attach to and invade host cells. Thus, humoral immunity is primarily concerned with fighting pathogens in extracellular spaces. However, pathogens that have already gained entry to host cells are largely protected from the humoral antibody-mediated defenses. Cellular immunity, on the other hand, targets and eliminates intracellular pathogens through the actions of T lymphocytes, or T cells (Figure (PageIndex{1})). T cells also play a more central role in orchestrating the overall adaptive immune response (humoral as well as cellular) along with the cellular defenses of innate immunity.

T Cell Production and Maturation

T cells, like all other white blood cells involved in innate and adaptive immunity, are formed from multipotent hematopoietic stem cells (HSCs) in the bone marrow (see [link]). However, unlike the white blood cells of innate immunity, eventual T cells differentiate first into lymphoid stem cells that then become small, immature lymphocytes, sometimes called lymphoblasts. The first steps of differentiation occur in the red marrow of bones (Figure (PageIndex{2})), after which immature T lymphocytes enter the bloodstream and travel to the thymus for the final steps of maturation (Figure (PageIndex{3})). Once in the thymus, the immature T lymphocytes are referred to as thymocytes.

The maturation of thymocytes within the thymus can be divided into tree critical steps of positive and negative selection, collectively referred to as thymic selection. The first step of thymic selection occurs in the cortex of the thymus and involves the development of a functional T-cell receptor (TCR) that is required for activation by APCs. Thymocytes with defective TCRs are removed by negative selection through the induction of apoptosis (programmed controlled cell death). The second step of thymic selection also occurs in the cortex and involves the positive selection of thymocytes that will interact appropriately with MHC molecules. Thymocytes that can interact appropriately with MHC molecules receive a positive stimulation that moves them further through the process of maturation, whereas thymocytes that do not interact appropriately are not stimulated and are eliminated by apoptosis. The third and final step of thymic selection occurs in both the cortex and medulla and involves negative selection to remove self-reacting thymocytes, those that react to self-antigens, by apoptosis. This final step is sometimes referred to as central tolerance because it prevents self-reacting T cells from reaching the bloodstream and potentially causing autoimmune disease, which occurs when the immune system attacks healthy “self” cells.

Despite central tolerance, some self-reactive T cells generally escape the thymus and enter the peripheral bloodstream. Therefore, a second line of defense called peripheral tolerance is needed to protect against autoimmune disease. Peripheral tolerance involves mechanisms of anergy and inhibition of self-reactive T cells by regulatory T cells. Anergy refers to a state of nonresponsiveness to antigen stimulation. In the case of self-reactive T cells that escape the thymus, lack of an essential co-stimulatory signal required for activation causes anergy and prevents autoimmune activation. Regulatory T cells participate in peripheral tolerance by inhibiting the activation and function of self-reactive T cells and by secreting anti-inflammatory cytokines.

It is not completely understood what events specifically direct maturation of thymocytes into regulatory T cells. Current theories suggest the critical events may occur during the third step of thymic selection, when most self-reactive T cells are eliminated. Regulatory T cells may receive a unique signal that is below the threshold required to target them for negative selection and apoptosis. Consequently, these cells continue to mature and then exit the thymus, armed to inhibit the activation of self-reactive T cells.

It has been estimated that the three steps of thymic selection eliminate 98% of thymocytes. The remaining 2% that exit the thymus migrate through the bloodstream and lymphatic system to sites of secondary lymphoid organs/tissues, such as the lymph nodes, spleen, and tonsils (Figure (PageIndex{3})), where they await activation through the presentation of specific antigens by APCs. Until they are activated, they are known as mature naïve T cells.

Exercise (PageIndex{1})

  1. What anatomical sites are involved in T cell production and maturation?
  2. What are the three steps involved in thymic selection?
  3. Why are central tolerance and peripheral tolerance important? What do they prevent?

Classes of T Cells

T cells can be categorized into three distinct classes: helper T cells, regulatory T cells, and cytotoxic T cells. These classes are differentiated based on their expression of certain surface molecules, their mode of activation, and their functional roles in adaptive immunity (Table (PageIndex{1})).

All T cells produce cluster of differentiation (CD) molecules, cell surface glycoproteins that can be used to identify and distinguish between the various types of white blood cells. Although T cells can produce a variety of CD molecules, CD4and CD8 are the two most important used for differentiation of the classes. Helper T cells and regulatory T cells are characterized by the expression of CD4 on their surface, whereas cytotoxic T cells are characterized by the expression of CD8.

Classes of T cells can also be distinguished by the specific MHC molecules and APCs with which they interact for activation. Helper T cells and regulatory T cells can only be activated by APCs presenting antigens associated with MHC II. In contrast, cytotoxic T cells recognize antigens presented in association with MHC I, either by APCs or by nucleated cells infected with an intracellular pathogen.

The different classes of T cells also play different functional roles in the immune system. Helper T cells serve as the central orchestrators that help activate and direct functions of humoral and cellular immunity. In addition, helper T cells enhance the pathogen-killing functions of macrophages and NK cells of innate immunity. In contrast, the primary role of regulatory T cells is to prevent undesirable and potentially damaging immune responses. Their role in peripheral tolerance, for example, protects against autoimmune disorders, as discussed earlier. Finally, cytotoxic T cells are the primary effector cells for cellular immunity. They recognize and target cells that have been infected by intracellular pathogens, destroying infected cells along with the pathogens inside.

Table (PageIndex{1}): Classes of T Cells
ClassSurface CD MoleculesActivationFunctions
Helper T cellsCD4APCs presenting antigens associated with MHC IIOrchestrate humoral and cellular immunity
Involved in the activation of macrophages and NK cells
Regulatory T cellsCD4APCs presenting antigens associated with MHC IIInvolved in peripheral tolerance and prevention of autoimmune responses
Cytotoxic T cellsCD8APCs or infected nucleated cells presenting antigens associated with MHC IDestroy cells infected with intracellular pathogens

Exercise (PageIndex{2})

  1. What are the unique functions of the three classes of T cells?
  2. Which T cells can be activated by antigens presented by cells other than APCs?

T-Cell Receptors

For both helper T cells and cytotoxic T cells, activation is a complex process that requires the interactions of multiple molecules and exposure to cytokines. The T-cell receptor (TCR) is involved in the first step of pathogen epitope recognition during the activation process.

The TCR comes from the same receptor family as the antibodies IgD and IgM, the antigen receptors on the B cell membrane surface, and thus shares common structural elements. Similar to antibodies, the TCR has a variable regionand a constant region, and the variable region provides the antigen-binding site (Figure (PageIndex{4})). However, the structure of TCR is smaller and less complex than the immunoglobulin molecules ([link]). Whereas immunoglobulins have four peptide chains and Y-shaped structures, the TCR consists of just two peptide chains (α and β chains), both of which span the cytoplasmic membrane of the T cell.

TCRs are epitope-specific, and it has been estimated that 25 million T cells with unique epitope-binding TCRs are required to protect an individual against a wide range of microbial pathogens. Because the human genome only contains about 25,000 genes, we know that each specific TCR cannot be encoded by its own set of genes. This raises the question of how such a vast population of T cells with millions of specific TCRs can be achieved. The answer is a process called genetic rearrangement, which occurs in the thymus during the first step of thymic selection.

The genes that code for the variable regions of the TCR are divided into distinct gene segments called variable (V), diversity (D), and joining (J) segments. The genes segments associated with the α chain of the TCR consist 70 or more different Vα segments and 61 different Jα segments. The gene segments associated with the β chain of the TCR consist of 52 different Vβ segments, two different Dβ segments, and 13 different Jβ segments. During the development of the functional TCR in the thymus, genetic rearrangement in a T cell brings together one Vα segment and one Jα segment to code for the variable region of the α chain. Similarly, genetic rearrangement brings one of the Vβ segments together with one of the Dβ segments and one of thetJβ segments to code for the variable region of the β chain. All the possible combinations of rearrangements between different segments of V, D, and J provide the genetic diversity required to produce millions of TCRs with unique epitope-specific variable regions.

Exercise (PageIndex{3})

  1. What are the similarities and differences between TCRs and immunoglobulins?
  2. What process is used to provide millions of unique TCR binding sites?

Activation and Differentiation of Helper T Cells

Helper T cells can only be activated by APCs presenting processed foreign epitopes in association with MHC II. The first step in the activation process is TCR recognition of the specific foreign epitope presented within the MHC II antigen-binding cleft. The second step involves the interaction of CD4 on the helper T cell with a region of the MHC II molecule separate from the antigen-binding cleft. This second interaction anchors the MHC II-TCR complex and ensures that the helper T cell is recognizing both the foreign (“nonself”) epitope and “self” antigen of the APC; both recognitions are required for activation of the cell. In the third step, the APC and T cell secrete cytokines that activate the helper T cell. The activated helper T cell then proliferates, dividing by mitosis to produce clonal naïve helper T cells that differentiate into subtypes with different functions (Figure (PageIndex{5})).

Activated helper T cells can differentiate into one of four distinct subtypes, summarized in Table (PageIndex{2}). The differentiation process is directed by APC-secreted cytokines. Depending on which APC-secreted cytokines interact with an activated helper T cell, the cell may differentiate into a T helper 1 (TH1) cell, a T helper 2 (TH2) cell, or a memory helper T cell. The two types of helper T cells are relatively short-lived effector cells, meaning that they perform various functions of the immediate immune response. In contrast, memory helper T cells are relatively long lived; they are programmed to “remember” a specific antigen or epitope in order to mount a rapid, strong, secondary response to subsequent exposures.

TH1 cells secrete their own cytokines that are involved in stimulating and orchestrating other cells involved in adaptive and innate immunity. For example, they stimulate cytotoxic T cells, enhancing their killing of infected cells and promoting differentiation into memory cytotoxic T cells. TH1 cells also stimulate macrophages and neutrophils to become more effective in their killing of intracellular bacteria. They can also stimulate NK cells to become more effective at killing target cells.

TH2 cells play an important role in orchestrating the humoral immune response through their secretion of cytokines that activate B cells and direct B cell differentiation and antibody production. Various cytokines produced by TH2 cells orchestrate antibody class switching, which allows B cells to switch between the production of IgM, IgG, IgA, and IgE as needed to carry out specific antibody functions and to provide pathogen-specific humoral immune responses.

A third subtype of helper T cells called TH17 cells was discovered through observations that immunity to some infections is not associated with TH1 or TH2 cells. TH17 cells and the cytokines they produce appear to be specifically responsible for the body’s defense against chronic mucocutaneous infections. Patients who lack sufficient TH17 cells in the mucosa (e.g., HIV patients) may be more susceptible to bacteremia and gastrointestinal infections.1

Table (PageIndex{2}): Subtypes of Helper T Cells
SubtypeFunctions
TH1 cellsStimulate cytotoxic T cells and produce memory cytotoxic T cells
Stimulate macrophages and neutrophils (PMNs) for more effective intracellular killing of pathogens
Stimulate NK cells to kill more effectively
TH2 cellsStimulate B cell activation and differentiation into plasma cells and memory B cells
Direct antibody class switching in B cells
TH17 cellsStimulate immunity to specific infections such as chronic mucocutaneous infections
Memory helper T cells“Remember” a specific pathogen and mount a strong, rapid secondary response upon re-exposure

Activation and Differentiation of Cytotoxic T Cells

Cytotoxic T cells (also referred to as cytotoxic T lymphocytes, or CTLs) are activated by APCs in a three-step process similar to that of helper T cells. The key difference is that the activation of cytotoxic T cells involves recognition of an antigen presented with MHC I (as opposed to MHC II) and interaction of CD8 (as opposed to CD4) with the receptor complex. After the successful co-recognition of foreign epitope and self-antigen, the production of cytokines by the APC and the cytotoxic T cell activate clonal proliferation and differentiation. Activated cytotoxic T cells can differentiate into effector cytotoxic T cells that target pathogens for destruction or memory cells that are ready to respond to subsequent exposures.

As noted, proliferation and differentiation of cytotoxic T cells is also stimulated by cytokines secreted from TH1 cells activated by the same foreign epitope. The co-stimulation that comes from these TH1 cells is provided by secreted cytokines. Although it is possible for activation of cytotoxic T cells to occur without stimulation from TH1 cells, the activation is not as effective or long-lasting.

Once activated, cytotoxic T cells serve as the effector cells of cellular immunity, recognizing and kill cells infected with intracellular pathogens through a mechanism very similar to that of NK cells. However, whereas NK cells recognize nonspecific signals of cell stress or abnormality, cytotoxic T cells recognize infected cells through antigen presentation of pathogen-specific epitopes associated with MHC I. Once an infected cell is recognized, the TCR of the cytotoxic T cell binds to the epitope and releases perforin and granzymes that destroy the infected cell (Figure (PageIndex{6})). Perforin is a protein that creates pores in the target cell, and granzymes are proteases that enter the pores and induce apoptosis. This mechanism of programmed cell death is a controlled and efficient means of destroying and removing infected cells without releasing the pathogens inside to infect neighboring cells, as might occur if the infected cells were simply lysed.

In this video, you can see a cytotoxic T cell inducing apoptosis in a target cell.

Exercise (PageIndex{4})

  1. Compare and contrast the activation of helper T cells and cytotoxic T cells.
  2. What are the different functions of helper T cell subtypes?
  3. What is the mechanism of CTL-mediated destruction of infected cells?

Superantigens and Unregulated Activation of T Cells

When T cell activation is controlled and regulated, the result is a protective response that is effective in combating infections. However, if T cell activation is unregulated and excessive, the result can be a life-threatening. Certain bacterial and viral pathogens produce toxins known as superantigens (see Virulence Factors of Bacterial and Viral Pathogens) that can trigger such an unregulated response. Known bacterial superantigens include toxic shock syndrome toxin (TSST), staphylococcal enterotoxins, streptococcal pyrogenic toxins, streptococcal superantigen, and the streptococcal mitogenic exotoxin. Viruses known to produce superantigens include Epstein-Barr virus (human herpesvirus 4), cytomegalovirus (human herpesvirus 5), and others.

The mechanism of T cell activation by superantigens involves their simultaneous binding to MHC II molecules of APCs and the variable region of the TCR β chain. This binding occurs outside of the antigen-binding cleft of MHC II, so the superantigen will bridge together and activate MHC II and TCR without specific foreign epitope recognition (Figure (PageIndex{7})). The result is an excessive, uncontrolled release of cytokines, often called a cytokine storm, which stimulates an excessive inflammatory response. This can lead to a dangerous decrease in blood pressure, shock, multi-organ failure, and potentially, death.

Exercise (PageIndex{5})

  1. What are examples of superantigens?
  2. How does a superantigen activate a helper T cell?
  3. What effect does a superantigen have on a T cell?

Clinical: SUPERANTIGENS

Melissa, an otherwise healthy 22-year-old woman, is brought to the emergency room by her concerned boyfriend. She complains of a sudden onset of high fever, vomiting, diarrhea, and muscle aches. In her initial interview, she tells the attending physician that she is on hormonal birth control and also is two days into the menstruation portion of her cycle. She is on no other medications and is not abusing any drugs or alcohol. She is not a smoker. She is not diabetic and does not currently have an infection of any kind to her knowledge.

While waiting in the emergency room, Melissa’s blood pressure begins to drop dramatically and her mental state deteriorates to general confusion. The physician believes she is likely suffering from toxic shock syndrome (TSS). TSS is caused by the toxin TSST-1, a superantigen associated with Staphylococcus aureus, and improper tampon use is a common cause of infections leading to TSS. The superantigen inappropriately stimulates widespread T cell activation and excessive cytokine release, resulting in a massive and systemic inflammatory response that can be fatal.

Vaginal or cervical swabs may be taken to confirm the presence of the microbe, but these tests are not critical to perform based on Melissa’s symptoms and medical history. The physician prescribes rehydration, supportive therapy, and antibiotics to stem the bacterial infection. She also prescribes drugs to increase Melissa’s blood pressure. Melissa spends three days in the hospital undergoing treatment; in addition, her kidney function is monitored because of the high risk of kidney failure associated with TSS. After 72 hours, Melissa is well enough to be discharged to continue her recovery at home.

Exercise (PageIndex{6})

In what way would antibiotic therapy help to combat a superantigen?

Clinical Focus: Part 2

Olivia’s swollen lymph nodes, abdomen, and spleen suggest a strong immune response to a systemic infection in progress. In addition, little Olivia is reluctant to turn her head and appears to be experiencing severe neck pain. The physician orders a complete blood count, blood culture, and lumbar puncture. The cerebrospinal fluid (CSF) obtained appears cloudy and is further evaluated by Gram stain assessment and culturing for potential bacterial pathogens. The complete blood count indicates elevated numbers of white blood cells in Olivia’s bloodstream. The white blood cell increases are recorded at 28.5 K/µL (normal range: 6.0–17.5 K/µL). The neutrophil percentage was recorded as 60% (normal range: 23–45%). Glucose levels in the CSF were registered at 30 mg/100 mL (normal range: 50–80 mg/100 mL). The WBC count in the CSF was 1,163/mm3 (normal range: 5–20/mm3).

Exercise (PageIndex{7})

  1. Based on these results, do you have a preliminary diagnosis?
  2. What is a recommended treatment based on this preliminary diagnosis?

Key Concepts and Summary

  • Immature T lymphocytes are produced in the red bone marrow and travel to the thymus for maturation.
  • Thymic selection is a three-step process of negative and positive selection that determines which T cells will mature and exit the thymus into the peripheral bloodstream.
  • Central tolerance involves negative selection of self-reactive T cells in the thymus, and peripheral toleranceinvolves anergy and regulatory T cells that prevent self-reactive immune responses and autoimmunity.
  • The TCR is similar in structure to immunoglobulins, but less complex. Millions of unique epitope-binding TCRs are encoded through a process of genetic rearrangement of V, D, and J gene segments.
  • T cells can be divided into three classes—helper T cells, cytotoxic T cells, and regulatory T cells—based on their expression of CD4 or CD8, the MHC molecules with which they interact for activation, and their respective functions.
  • Activated helper T cells differentiate into TH1, TH2, TH17, or memory T cell subtypes. Differentiation is directed by the specific cytokines to which they are exposed. TH1, TH2, and TH17 perform different functions related to stimulation of adaptive and innate immune defenses. Memory T cells are long-lived cells that can respond quickly to secondary exposures.
  • Once activated, cytotoxic T cells target and kill cells infected with intracellular pathogens. Killing requires recognition of specific pathogen epitopes presented on the cell surface using MHC I molecules. Killing is mediated by perforin and granzymes that induce apoptosis.
  • Superantigens are bacterial or viral proteins that cause a nonspecific activation of helper T cells, leading to an excessive release of cytokines (cytokine storm) and a systemic, potentially fatal inflammatory response.

Multiple Choice

What is a superantigen?

A. a protein that is highly efficient at stimulating a single type of productive and specific T cell response
B. a protein produced by antigen-presenting cells to enhance their presentation capabilities
C. a protein produced by T cells as a way of increasing the antigen activation they receive from antigen-presenting cells
D. a protein that activates T cells in a nonspecific and uncontrolled manner

D

To what does the TCR of a helper T cell bind?

A. antigens presented with MHC I molecules
B. antigens presented with MHC II molecules
C. free antigen in a soluble form
D. haptens only

B

Cytotoxic T cells will bind with their TCR to which of the following?

A. haptens only

A

A ________ molecule is a glycoprotein used to identify and distinguish white blood cells.

A. T-cell receptor
B. B-cell receptor
C. MHC I
D. cluster of differentiation

D

Name the T helper cell subset involved in antibody production.

A. TH1
B. TH2
C. TH17
D. CTL

B

Fill in the Blank

A ________ T cell will become activated by presentation of foreign antigen associated with an MHC I molecule.

cytotoxic

A ________ T cell will become activated by presentation of foreign antigen in association with an MHC II molecule.

helper

A TCR is a protein dimer embedded in the plasma membrane of a T cell. The ________ region of each of the two protein chains is what gives it the capability to bind to a presented antigen.

variable

Peripheral tolerance mechanisms function on T cells after they mature and exit the ________.

thymus

Both ________ and effector T cells are produced during differentiation of activated T cells.

memory

Short Answer

What is the basic difference in effector function between helper and cytotoxic T cells?

What necessary interactions are required for activation of helper T cells and activation/effector function of cytotoxic T cells?

Footnotes

  1. 1 Blaschitz C., Raffatellu M. “Th17 cytokines and the gut mucosal barrier.” J Clin Immunol. 2010 Mar; 30(2):196-203. doi: 10.1007/s10875-010-9368-7.

TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action

Cancer immunotherapy has produced impressive clinical results in recent years. Despite the success of the checkpoint blockade strategies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1), a large portion of cancer patients have not yet benefited from this novel therapy. T cell immunoglobulin and mucin domain 3 (TIM-3) has been shown to mediate immune tolerance in mouse models of infectious diseases, alloimmunity, autoimmunity, and tumor Immunity. Thus, targeting TIM-3 emerges as a promising approach for further improvement of current immunotherapy. Despite a large amount of experimental data showing an immune suppressive function of TIM-3 in vivo, the exact mechanisms are not well understood. To enable effective targeting of TIM-3 for tumor immunotherapy, further in-depth mechanistic studies are warranted. These studies will also provide much-needed insight for the rational design of novel combination therapy with other checkpoint blockers. In this review, we summarize key evidence supporting an immune regulatory role of TIM-3 and discuss possible mechanisms of action.

Keywords: T cell subsets TIM-3 antitumor immune responses tumor microenvironment.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

T cell immunoglobulin and mucin…

T cell immunoglobulin and mucin domain 3 (TIM-3), its ligands, and signaling adaptor…

Summary of multiple biological functions…

Summary of multiple biological functions of TIM-3 on various immune cells. TIM-3 signaling…


7 Important Cells of Immune System | Immunology

The following points highlight the seven important cells of immune system. The cells are: 1. Hematopoietic Stem Cell 2. Lymphocytes 3. Monocytes 4. Macrophages 5. Granulocytes 6. Dendritic Cells 7. Mast Cells.

Cell # 1. Hematopoietic Stem Cell:

All blood cells arise from a type of cell called hematopoietic stem cell (HSC) (or stem cell). The stem cells are self-renewing, maintain their population by cell division, and differentiate into other cell types. This process of formation and development of blood cells (red and white blood cells) is called hematopoiesis.

It is remarkable that every functionally specialised, mature blood cell is derived from the same type of hematopoietic stem cell. In contrast to a unipotent cell, which differentiates into a single cell type, a hematopoietic stem cell is multi-potent or pluripotent as it is able to differentiate in various ways and thereby gives rise to various type of blood cells.

In humans, the formation and development of blood cells begins in the embryonic yolk sac during the first weeks of development. The hematopoietic stem cells differentiate into primitive erythroid cells that contain embryonic haemoglobin. In the third month of gestation, hematopoietic stem cells migrate from the yolk sac to the foetal liver and then to the spleen.

Liver and spleen play major roles in hematopoiesis from the third to the seventh months of gestation. In later months, hematopoietic stem cells differentiate in the bone marrow and play major role in hematopoiesis, and by birth there is little or no hematopoiesis in the liver and spleen.

Multi-potent hematopoietic stem cell (or stem cell) in the bone marrow differentiates to form two lineages:

(1) Common-lymphoid progenitor cell and

(2) Common myeloid progenitor cell (Fig. 42.7).

The progenitor cells, unlike hematopoietic stem cell that is self-renewing, loss the capacity for self-renewal, and are committed to their specific cell linkage.

The common lymphoid progenitor cells give rise to B-lymphocytes (B-cells) that differentiate into antibody secreting plasma cells. T-lymphocytes (T-cells) that become activated T-cells. natural killer (NK) cells, and some dentritic cells.

The common myeloid progenitor cells give rise to erythroblasts that produce erythrocytes (red blood cells), megakaryoblasts that produce platelets (thrombocytes), myeloblasts that produce granulocytes (eosinophils, basophils, neutrophils), monoblasts that differentiate into monocytes which give rise to macrophages and dendritic cells, and an unknown precursor that produces mast cells.

However, B-lymphocytes (B-cells) T-lymphocytes (T-cells) and natural killer (NK) cells produced by lymphoid progenitor cell lineage and eosinophils, basophils, neutrophils, macrophages, and dendritic cells produced by myeloid progenitor cell lineage are collectively called white blood cells or leucocytes (Gk. leucos = white, kytos = cell). White blood cells or leucocytes are the cells that are responsible for nonspecific and specific immunity in the body.

Cell # 2. Lymphocytes:

Lymphocytes (L. lympha = water, cyte = cell) are the most important effector cells of many cells involved in specific immune response. These cells are small, round and 5-15 μm in diameter. They are found in peripheral blood, lymph, lymphoid organs, and in many other tissues. Lymphocytes constitute 20% – 40% of the white blood cell (leucocyte) population in the body and 99% of the cells in the lymph.

They may be small (5-8 μm), medium (8-12 μm). and large (12-15 μm). The small lymphocytes are more numerous and may be short-lived with a life-span about two weeks or long-lived with a life-span of three years or more or even for life.

Short­-lived lymphocytes act as effector cells in immune response, while long-lived ones function as memory cells. Long-lived lymphocytes are mainly thymus derived. The formation and development of lymphocytes, i.e.. lymphopoiesis takes place in bone marrow, primary or central lymphoid organs, and secondary or peripheral lymphoid organs.

Lymphocytes are approximately 10 11 in number in a human body their number ranges from 10 10 to 10 12 depending on body size and age. Lymphocytes can be broadly subdivided into three populations: B-lymphocytes or B-cells, T-lymphocytes or T-cells, and null cells (natural killer cells or NK cells are included in this group).

1. B-Lymphocytes or B-Cells:

B-lymphocytes or B-cells derive their name from their site of maturation. They are so named since they were first detected in the bursa of Fabricius of birds and later from bone marrow of a number of mammalian species, including humans and mice. In birds, the multi-potent hematopoietic stem cells originating in the bone marrow migrate to the bursa of Fabricius and differentiate there into antibody synthesizing cells.

The bursa is a small pouch-like organ in the embryonic hind-gut of birds and is absent in mammals. In a number of mammalian species including humans and mice, the B-cells originate in the foetal lever and later migrate to the bone marrow which becomes the site for production of B-cells after embryonic life.

B-lymphocytes do not have the ability to synthesize antibody molecule during undifferentiated stage. During differentiation, each lymphocyte acquires the ability to synthesize antibody molecules when provoked by antigens.

2. T-Lymphocytes or T-Cells:

T-Lymphocytes or T-cells derive their name from their site of maturation in the thymus. They are major players in the cell-mediated immune response and also have an important role in B-cell activation. T-cells themselves do not secrete antibodies (immunoglobulin) like B-cells.

They are immunologically specific and are directly involved in cell-mediated immune responses, can carry a vast repertoire of immunologic memory, and can function in a variety of effector and regulatory way.

The main effector functions include tuberculin reaction (delay-ed hypersensitivity response), destruction of tissue grafts, secretion of soluble chemical mediators called lymphokines and their ability to perform killer functions of other cells.

The regulatory functions involve their cooperation with B-lymphocytes to produce antibodies. In additions to these functions, some subpopulations of T-cells contribute immune responses such as cytotoxicity, suppression, and killer properties.

Like B-lymphocytes, T-lymphocytes have specific receptors on the plasma membrane surface for antigen. The receptors on T-cell membrane are called T-cell receptors (TCRs).

Although T-cell receptor (TCR) is structurally distinct from immuno-globulin (the membrane receptor of B-lymphocyte), it does share some common structural features with the immunoglobulin molecule, most notably in the structure of its antigen- binding site.

Unlike the membrane-bound antibody on B-cells that recognise free antigen, the T-cell receptor (TCR) does not recognize free antigen instead it recognizes the hound one to particular class of a self-molecule (e.g., major histocompatibility complex molecule or MHC molecule) displayed on self-cells (e.g., antigen presenting cells or APCs, virus-infected cells, cancer cells, and grafts). It is the T-cell system that helps eliminating these altered self-cells that threaten the normal functioning of the body.

Cell # 3. Monocytes:

Monocytes (G. monos = single cyte = cell) are mononuclear phagocytic leucocytes possessing an oval or kidney-shaped nucleus and granules in the cytoplasm that stain grey-blue (Fig. 42.8).

Monocytes are produced in bone marrow. During hematopoiesis in bone marrow, granulocyte-monocyte progenitor cells differentiate into pro-monocytes, which-leave the bone marrow and enter the blood where they further differentiate into mature monocytes.

Mature monocytes circulate in the blood stream for about eight hours, enlarge in size, migrate into the tissues, and differentiate into specific tissue macrophages or into myeloid dendritic cells.

Cell # 4. Macrophages:

Macrophages (G. macros = large phagein = to eat), as noted above, are differentiated from monocytes into the tissues of the body.

Differentiation of a monocyte into a tissue macrophage (Fig. 42.9) involves a number of changes:

(i) The monocyte enlarges five- to ten-fold,

(ii) Its intracellular organelles increase in both number (especially lysosomes and phagolysosomes) and complexity,

(iii) The cell acquires increased phagocytic ability,

(iv) Produces higher levels of hydrolytic enzymes,

(v) Begins to secrete a variety of soluble factors, and

(vi) Develops ruffles or microvilli on the surface of its plasma membrane.

Macrophages are transported throughout the body. Some macrophages reside in particular tissues and become fix macrophages. Others remain motile by amoeboid movement throughout the body and are called free or wondering macrophages.

Macrophages serve different functions i different tissues and are named according to their tissue location, e.g., histiocytes in connective tissues, osteoclasts in bone, microglial cells in the brain, alveolar macrophages in the lung, kupffer cells in the liver, and mesangial cells in the kidney.

Macrophages normally remain in a resting state and are activated for effective functioning. They are activated by a variety of stimuli such as interferon gamma (IFN-γ) secreted by activated T helper (TH) cells, mediators of inflammatory response, components of bacterial cell walls, etc.

Activated macrophages secrete different types of cytotoxic proteins that help them eliminate large number of pathogens including vims-infected cells, malignant cells, and intracellular bacteria.

Activated macrophages also display class II MHC molecules that allow them to act more effectively as antigen-presenting cells (APCs). Thus, macrophages and T helper (TH) cells facilitate each other’s activation during the immune response.

Macrophages are highly phagocytic and they are capable of ingesting and digesting exogenous antigens (e.g., whole microorganisms and insoluble particles) and exogenous matter (e.g., injured or dead host cells, cellular debris, activated clotting factors).

Cell # 5. Granulocytes:

Granulocytes (Fig. 42.10) are those white blood cells (leucocytes) which have irregular-shaped nuclei with two to five lobes and granulated cytoplasmic matrix.

Granules of cytoplasmic matrix contain reactive substances that kill microorganisms and enhance inflammation. Granulocytes are also called polymorphonuclear leucocytes (PMNs). Three types of granulocytes are recognised in the body and they are: basophils, eosinophils, and neutrophils.

Basophils (G. basis = base philein = to love) possess bi-lobed irregular-shaped nucleus and cytoplasmic matrix granules that stain bluish-black with basic dyes (e.g., methylene blue). These granulocytes are non-phagocytic cell that function by releasing pharmacologically active substances (e.g., histamine, prostaglandins, serotonin, and leucotrienes) from their cytoplasmic granules upon appropriate stimulation.

Since these pharmacologically active substances influence the tone and diameter of blood vessels, they are collectively termed vasoactive mediators. Basophils possess high-affinity receptors for immunoglobulin-E (IgE) antibody and thereby become coated with these antibodies.

Once coated, antigens trigger the basophil cells to secrete vasoactive mediators which are inflammatory and play a major role in certain allergic responses (e.g., eczema, hay fever, and asthma). Basophils, however, comprise less than 1 % of white blood cells, are non-motile, and remain confined to the blood stream.

Eosinophils (G. eos = dawn philein = to love) have a bi-lobed nucleus connected by a slender thread of chromatin and prominent acidophilic granules in cytoplasmic matrix. Eosinophils, like neutrophils, are motile cells that migrate from bloodstream into tissue spaces.

These granulocytes are considered to play a role in the defence against parasitic organisms (protozoans and helminth parasites) by phagocytosis.

They release mainly cationic proteins and reactive oxygen metabolites into the extracellular fluid. These substances damage the plasma membrane of the parasite. Eosinophils constitute only 3-5% of the white blood cells and their acidophilic granules stain red with acidic dyes.

Neutrophils (L. neuter – neither philein = to love) possess a three- to five-lobed nucleus connected by slender threads of chromatin, and contain fine primary and secondary granules in cytoplasmic matrix. Neutrophils, like eosinophils, are motile cells that migrate from bloodstream into the tissue.

These granulocytes circulate in the bloodstream for 7 to 10 hours before their migration into the tissues where they enjoy a life span of only a few days. Approximately 60% of the circulating white blood cells (leucocytes) in human are the neutrophils. Like macrophages, the’ primary function of neutrophils is phagocytosis of foreign or dead cells and pinnocytosis of pathological immune complexes.

Phagocytosis by neutrophils is similar to that operated by macrophages except that the lytic enzymes and bactericidal substances in neutrophils are contained within primary and secondary granules instead of lysosomes in macrophages. The primary granules are larger and denser and contain peroxidase, lysozyme, and various hydrolytic enzymes.

The secondary granules are smaller and contain collagenase, lactoferrin, and lysozyme. Both primary and secondary granules fuse with phagosome, whose contents are then digested and the remains excreted much as they are in macrophages.

Neutrophils, like macrophages, also use oxygen-dependent and oxygen-independent pathways to generate antimicrobial substances and defensins to kill ingested microorganisms. Neutrophils generate more reactive oxygen intermediates and reactive nitrogen intermediates and express higher levels of defensins than macrophages do.

Cell # 6. Dendritic Cells:

Dendritic cells constitute only 0.2% of WBCs (leucocytes) in the blood and are present in even smaller numbers in skin and mucous membranes of the nose, lungs, and intestines. They derive their name due to long membrane extensions resembling the dendrites of nerve cells.

Dendritic cells arise from hematopoietic stem cells in the bone marrow via different pathways and in different locations (Fig. 42.11) they descend through both the myeloid and lymphoid lineages. Stem cell-originated dendritic cells are of four types: Langerhans cells, interstitial dendritic cells, myeloid dendritic cells, and lymphoid dendritic cells.

Despite differences, all the stem cell-originated mature dendritic cells perform the same major function of presenting antigen to T helper (TH) cells by expressing high levels of both class II MHC molecules and members of the co-stimulatory B-7 family, and thereby play an important accessory role in the specific immune response.

This pattern of functioning makes dendritic cells more potent antigen-presenting cells (APCs) than macrophages and B-lymphocytes, both of which need to be activated before they can function as antigen-presenting cells (APCs).

In addition to dendritic cells originated in bone marrow, there are another type of dendritic cells, the follicular dendritic cells, that do not arise in bone marrow and perform their function in a different ways as they do not express class II MHC molecules and do not act as antigen-presenting cells (APCs).

Follicular dendritic cells express high levels of membrane receptors for antibody which allows the binding of antibody complexes. The interaction of B-lymphocytes with this bound antigen can have important effects on B-lymphocyte responses.

Cell # 7. Mast Cells:

Mast cell precursors originate in the bone marrow and are released into the blood as undifferentiated cells. Mast cells are not differentiated from their precursors until the latter leave the blood and enter the tissues. Mast cells are found in a variety of tissues including the skin, connective tissues of various organs, and mucosal epithelial tissue of the respiratory, genitourinary, and digestive tracts.

These cells, like basophils, possess large numbers of granules in cytoplasmic matrix. The granules in cytoplasm contain histamine and other pharmacologically active substances that contribute to the inflammatory response. Mast cells, together with basophils, play an important role in the development of allergies and hypersensitivities.


T-lymphocytes (T cells)

Ontogeny

The process of development and maturation of the T Cells in mammals begins with the haematopoietic stem cells (HSC) in the fetal liver and later in the bone marrow where HSC differentiate into multipotent progenitors. A subset of multipotent progenitors initiates the transcription of recombination activating gene 1 and 2 (RAG 1 and RAG2) and become lymphoid-primed multipotent progenitors and then common lymphoid progenitors (CLP). Only a small subset of pluripotent cells migrates to the thymus and differentiates into early thymic progenitors (ETP). The thymus does not contain self-renewing progenitors and therefore, long-term thymopoiesis depends on the recruitment of thymus-settling progenitors throughout the life of the individual (1). These progenitors must enter the thymus to become gradually reprogrammed into fully mature and functional T Cells. The T Cell’s distinct developmental steps, as illustrated in Figure 1, are coordinated with the migration of the developing thymocytes towards specific niches in the thymus that provide the necessary stage-specific factors that are needed for further differentiation.

Figure 1

Overview of T Cell development and maturation. Adapted from Rothenberg et al. (4). Abbreviations. HSC: Haematopoietic stem cells, CLP: Common lymphoid progenitors, ETP: Early thymic progenitors, DN: Double negative DP: Double positive, SP: Single positive, (more. )

The ETP are multipotent and can generate T Cells, B Cells, Natural killer cells (NK), myeloid cells, and dendritic cells (DC). ETP represent a small and heterogenous subset, have the ability to proliferate massively, and can be identified by the phenotype Lin low , CD25 − , Kit high as well as by their expression of Flt3, CD24, and CCR9 (1). These cells, which are attracted by the chemokines CCL19 and CCL21, enter the thymus via the corticomedullar junction. In the stroma of the thymus, the ETP encounter a large number of ligands for the Notch receptors as well as growth factors such as Kit-ligand and IL-7 which trigger and support the differentiation and proliferation of these cells in the initial stages of T Cell development (2). Moreover, the expression of Notch-1 receptors and their interaction with Delta-like ligands is essential for the differentiation of the T Cells in the thymus and for the inhibition of the non-T Cell lineage development (3).

Within the thymic cortex, ETP differentiate into double negative (DN) cells that do not express either CD4 or CD8 (i.e., CD4 − and CD8 − ). Some authors consider the ETP a DN1 cell that later differentiates into DN2 when it acquires the CD25 + and CD44 + receptors. At this stage of development, the cells lose the B potential and begin to express proteins that are critical for the subsequent T Cell receptor (TCR) gene rearrangement such as RAG1 and RAG2. They also begin to express proteins necessary for TCR assembly and signaling as CD3 chains, kinases, and phosphatases such as LCK, ZAP70, and LAT (4). DN3 cells can take two divergent routes of differentiation. A cell can either express the αβ chains of the TCR and follow the process of selection to generate CD4 + or CD8 + T Cells or express the γδ chains to generate a subpopulation of γδ lymphocytes with special functional characteristics (5,6) (Table 1).

Table 1

Characteristics of αβ T cells and γδ T cells.

The expression of the β chain of TCR, at the DN3 stage, cascades the simultaneous expression of the CD4 and CD8 molecules and thus, the cells convert into double positives (DP), which constitutes the largest population of cells in the thymus (4,7). At this stage of maturation, the DP cells enter a control point known as positive selection to select the cells with functional TCRs that bind to self-peptides with intermediate affinity and avidity. For this, the epithelial cells of the thymic cortex “put the DP cells to the test” by presenting their own peptides in the context of the class I (HLA-I) and class II (HLA-II) HLA molecules. Only a fraction (1%-5%) of the DP cells, that express a TCR with intermediate affinity for these Ags persists by survival signals. DP cells incapable of binding HLA-I or HLA-II undergo apoptosis. Positive selection allows the differentiation of the DP thymocytes towards a single positive (SP) population that is restricted to HLA (i.e., DP cells that recognize HLA-I differentiate into CD4 − CD8 + and those that recognize HLA-II differentiate into CD4 + CD8 − ) (8, 9). Subsequently, SP cells enter the medulla of the thymus where a second control point known as negative selection takes place. At the medulla, positively selected thymocytes are exposed to a diverse set of self-antigens presented by medullary thymic epithelial cells (mTEC) and DC. mTECs use a special epigenetic mechanism to give rise to what is often referred to as promiscuous gene expression which contributes to the low expression of many genes including tissue-restricted self-antigens. SP cells with a high affinity or avidity for binding self peptides presented on HLA-I or HLA-II are eliminated by apoptosis, thus assuring the destruction of potentially autoreactive cells (9). Cells that survive negative selection mature and become naïve T Cells given the fact that they have not been primed by Ag for which they express a specific TCR. Naïve T Cells leave the thymus and migrate continuously to the secondary lymphoid organs to be primed and differentiate into effector cells with specialized phenotypes.

T cell receptor (TCR) complex

During the maturation process, T Cells acquire a receptor called TCR that recognizes a specific Ag. TCR is a multiprotein complex composed of two variable antigen-binding chains, αβ or γδ, which are associated with invariant accessory proteins (CD3γε, CD3δε, and CD247 ζζ chains) that are required for initiating signaling when TCR binds to an Ag (10).

The αβ-TCR does not recognize Ag in its natural form but recognizes linear peptides which have been processed and presented in the HLA-I or HLA-II context. The peptides presented by HLA-I molecules are small (8� aminoacids) and have an intracellular origin while those presented by HLA-II molecules are longer (13� aminoacids) and are generally of extracellular origin. Nevertheless, the αβ-TCR of NKT cells and the γδ-TCR can recognize glycolipids and phospholipids presented by CD1 molecules.

TCR α and β chains are very polymorphic, which favors the recognition of a great diversity of peptides. Each chain has a variable (V) and a constant domain (C) with a joining segment (J) that lies between them. The β chain also has an additional diversity segment (D). Each (V) domain has three hypervariable sectors known as CDR-1, -2, and -3 (complementarity-determining regions) and is capable of generating an inmense pool of combinations to produce different TCR specific for an Ag. CDR3α and β regions bind to the central region of the peptide presented. This region represents the most diverse region of the TCR and is considered to be the main determinant of specificity in Ag recognition. CDR1α and β also contribute to peptide recognition and bind to it through the amino and carboxy-terminal motifs respectively. TCR regions that come into contact with HLA mainly correspond to CDR-1 and CDR-2 (10). TCR associates with a molecule called CD3, which is composed of three different chains: gamma, delta, and epsilon γδε. These chains are associated as heterodimers γε and δε. TCR is also associated with a homodimer of δε chains (CD247) that has a long intracytoplasmic portion and participates in the downstream transductional activation signals. Both the CD3 chains and the δε chains that associate with TCR possess tyrosine-based activation motifs (ITAMs) in their intracytoplasmic moeities, which are phosphorylated to initiate T Cell activation (11).

TCR gene rearrangement is essential during T Cell development. Multiple gene segments dispersed in the genomic DNA must bind and transcribe to produce a functional TCR. This process occurs independently for each chain beginning with the recombination of genes for the β chain (12). Genes that code for the TCR chains in humans map to four loci: TCRA and TCRD on chromosome 14 and TCRB and TCRG on chromosome 7. The locus for the β chain has 42 gene segments for the region (V), 2 for (D), 12 for (J), and 2 for (C) while the locus for the α chain has 43 gene segments for the region (V) and 58 for (J) (13) (Figure 2). Somatic recombination of these gene segments occurs at the DN2 and DN3 stages of T Cell development and is mediated by the gene products RAG-1 and RAG-2. Nuclease and ligase activity, as well as the addition or elimination of nucleotides, generates the great variety of TCR present in our organism at the moment of birth. It is estimated that the diversity of TCR in humans may reach 2󗄇 (13).

Figure 2

TCR generation by somatic recombination. Adapted from Turner et al. (13). Abbreviations. TCR: T Cell receptor C: constant gene segment, V: variable gene segment, D: diversity gene segment, J: junctional gene segment, N: addition of non-template-encoded (more. )

Activation of the naïve T cells

T Cell activation and differentiation will only be sucessfull if three signals are present: i) interaction of the TCR with the peptide presented by the HLA molecule, ii) signaling through co-stimulatory molecules, and iii) participation of cytokines that initiate clonal expansion (14).

Additionally, the cytokine microenvironment that accompanies the activation defines the type of response that will be generated later.

Ag recognition and signal transduction pathways in T cells

Constant migration of the naïve T Cells towards the secondary lymphoid organs is essential in order for each one to encounter its specific Ag presented by an antigen-presenting cell (APC) (15). For this to occur, the naïve T Cells constitutively express L-selectin, an adhesion molecule which acts on the initial binding of T Cells to the high endothelial postcapillary venules located in the lymph nodes, tonsils, and aggregated lymphatic follicles. Only the specialized endothelial cells in the post-capillary veins allow constant passage of the T Cells from the blood towards the lymph nodes or Peyer’s patches given that the latter two constitutively express the addressins PNAd (peripheral node addressin) or MAdCAM-1 (mucosal addressin cell adhesion molecule-1) respectively. Both interact with the L-selectin of the lymphocytes. The endothelial cells of the rest of the vasculature restrict or impede binding of lymphocytes unless their receptors are induced by inflammation mediators (16).

In the lymph nodes, T Cells establish temporary contact with a great number of dendritic cells (DC) but only halt and bind to those which present an Ag which is compatible and specific to their receptor (15).

T Cells within lymph nodes migrate at high speeds of about 11� μ per minute. This is in contrast to DCs which transit through lymph nodes at speeds of about 3𠄶 μ per minute and then stop. This allows DCs to constantly establish new contacts with T Cells. In the absence of Ag, T Cells do not stop, but in the presence of an Ag, the duration of the interaction with the DC may be transitory (3 - 11 min) or stable (several hours) depending on the affinity for the Ag (15). Stable unions are favored by the high presence of peptides in the DC, highly antigenic ligands, mature DC, and expression of molecules such as ICAM-1 (15).

Antigen recognition by TCR induces the formation of several “TCR microclusters” that accompany the reorganization and approach of other membrane molecules and signaling proteins towards the contact zone with the DC. This contact zone between the T Cell and DC membranes is known as an immunological synapse and consists of a highly organized and dynamic molecular complex divided into three concentric zones known as the central, peripheral, and distal supramolecular activation clusters. The central region is composed of the TCR complex, co-stimulatory and co-inhibitory molecules, and co-receptors. These co-receptors are known as primary and secondary activation signals. The peripheral zone is mainly made up of the adhesion molecules LFA-1-ICAM-1 and CD2-LFA-3 that, due to their affinity, maintain and stabilize binding between the cells. The distal zone consists of F-actin and phosphatase CD45 (17).

After Ag recognition, a complex signaling process is initiated on the internal side of the membrane and in the cytoplasm for the subsequent activation of three essential transcription factors: NFAT, AP-1, and NF-㮫. These signaling pathways are shown in a simplified diagram in Figure 3 and start when phosphatase CD45 activates the tyrosine-kinases, Fyn and Lck, which are associated with the ε chains of the CD3 and the co-receptors CD4/CD8 respectively (18). Once activated, these kinases autophosphorylate and phosphorylate the ITAM moieties of the δε chains and CD3. Phosphorylated ITAMs attract the ZAP-70 molecule. Then, the binding of ZAP-70 to phospholipase C 㬱 (PLC 㬱) or LAT initiates two different cascades.

Figure 3

Overview of TCR signalling pathways. Adapted from Brownlie et al. (18). Abbreviations. LCK: lymphocyte-specific protein tyrosine kinase, FYN: a member of Src tyrosine kinases, ZAP70: ζ-chain associated protein kinase of 70 kDa, LAT: Linker for (more. )

A first cascade is initiated when PLC- 㬱 converts the phosphatidylinositol biphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol (DAG). The IP3 diffuses into the cytoplasm and binds to the receptors of the endoplasmic reticulum, where it induces the release of Ca 2+ deposits to the cytosol. The intracellular increase of Ca 2+ stimulates the enzyme calmodulin, which is a serine/threonine-kinase. The activated calmodulin, in turn, activates calcineurin, a phosphatase that catalyzes the desphosphorylation of the nuclear transcription factor NF-AT to allow entry into the nucleus and activate the expression of several genes (e.g., IL-2, etc.) (19).

A second signaling cascade is initiated when ZAP-70 phosphorylates an adaptor protein known as LAT. LAT recruits several proteins that allow transference of guanine nucleotides from GDP to GTP for the activation of some proteins called Ras. These initiate a cascade of phosphorylations resulting in the activation of mitogen activated protein kinases (MAPK). These MAPK are tasked with activating the transcription factor AP-1 which is composed of the proteins c-fos and c-jun. MAPKs allow dimerization of those proteins to initiate the transcription of genes (18).

The third signaling pathway is initiated with the production of DAG, which activates protein kinase C (PKC). Later, it gives rise to recruitment of the IKK complex which requires the proteins Carma1, Bcl10, and MALT1 for its activation. Activation of the IKK kinases permits the phosphorylation of the I㮫 inhibitors, which are then ubiquitinated and degraded. This releases NF-㮫 dimers that translocate to the nucleus and activate transcription of their target genes (20).

The transcription factors NF-AT, AP-1, and NF-㮫 enter the nucleus and induce the transcription of genes to initiate the secretion of IL-2 the expression of its high affinity alpha receptor (IL-2Rα) the expression of integrins that promote cellular adhesion the expression of costimulatory molecules such as CD40L and the expression of anti-apoptotic proteins (19, 20).

Co-stimulation

A co-stimulatory molecule is defined as a surface molecule that is not itself able to activate T Cells but which can significantly amplify or reduce the signaling induced by the TCR complex (21,22). The main T Cell co-stimulatory molecules and their respective ligands for the profesional and non-professional APC are shown in Table 2.

Table 2

T Cell co-stimulatory molecules and their ligands.

Positive co-stimulatory signals are known as the second activation signal and are indispensable for potentiating the production of IL-2 due to the induction of a sustained activation of the nuclear transcription factor NF-㮫. Furthermore, interaction between these molecules initiates antiapoptotic signals that prolong T Cell life span and initiate the expression of adherence molecules as well as the production of growth factors and cytokines that promote their proliferation and differentiation.

Only CD28, CD27, and HVEM are expressed constitutively while the remaining co-stimulatory molecules are inducible and expressed only after activation. Constitutive co-stimulatory molecules have a positive regulatory effect (21, 22).

Although most of the co-stimulatory molecules have a monotypic binding (one ligand), some of them, e.g., CD28 and PD-1, interact with more than one ligand. Moreover, other molecules such as those of the SLAM family interact homotypically with identical molecules. Almost all of the T Cell co-stimulatory molecules belong to the CD28/B7 superfamily or the TNF/TNFR family (21, 22).

There is a hierarchy in the downstream activation of these co-stimulatory molecules. For example, it has been observed that co-stimulation with CD28 significantly increases the induction of ICOS and OX-40 on the surface of the T Cell (22).

Clonal expansion

In response to antigen recognition and co-stimulatory signals, T Cells initiate the synthesis of IL-2 and express the high affinity receptor for it (IL2Rα or CD25) transitorily. CD25 binds to the other chains of the IL2R which are the β chain (CD122) and common γ chain (CD132). However, it does not participate in the signaling, but increases the affinity for IL-2 from 10 to 100 times (23).

IL-2 acts as an autocrine and paracrine growth factor. IL-2 activates blastogenesis or clonal expansion which gives rise to large numbers of T Cells with receptors identical to the original, able to recognize only the Ag that initiated its activation. IL-15 and IL-21 also participate in this process of clonal expansion (23).

T Cell activation and clonal expansion is followed by a death phase during which 90% of the effector cells are eliminated by apoptosis. The mechanisms which induce this phase of contraction or death include interactions Fas-FasL, TNF, and TNFR I and II as well as CD40-CD40L. In addition, molecules such as perforins, IFN- γ, and IL-2 regulate the contraction phase of the T Cells (24).

CD4 + T cell subsets

The differentiation of a CD4 + T Cell into distinct subpopulations or cell phenotypes is determined by the nature and concentration of the Ag, the type of APC and its activation state, the cytokine microenvironment that accompanies the antigenic presentation, and the presence and quantity of co-stimulatory molecules, along with other variables.

If the T Cell expresses CD4, it is converted into a T-helper cell (Th) which has a double function: to produce cytokines and to stimulate B Cells to generate Abs. Until recently, only four distinct phenotypes had been identified: Th1, Th2, Th17, and T-regulatory cells (Treg) each of which secretes a different cytokine profile. However, in the last few years, new T-helper subsets such as Th9, Th22, and follicular helpers (Tfh) have been identified. Figure 4 summarizes the main characteristics of these T Cell subsets, the factors that induce them, and the cytokines they produce.

Figure 4

CD4 T Cell subsets. Adapted from Lloyd et al. (30). Abbreviations. TH: T-helper, IFNγ: interferon gamma, DTH: delayed type hypersensitivity, TNF: tumor necrosis factor, FGF: fibroblast growth factor, AHR: airway hyperresponsiveness.

Th1. The differentiation of the Th1 cells is induced by IL-12, IL-18, and type 1 IFNs (IFN-α and IFN-β) secreted by DC and macrophages after being activated by intracellular pathogens. IL-18 potentiates the action of IL-12 on the development of the Th1 phenotype. In general, the response mediated by Th1 depends on the T-bet transcription factor and the STAT4 molecule. These cells produce IFN- γ, IFN-α, IFN-β, and IL-2 and express CXCR3 and CD161 (25). They stimulate strong cell immunity to intracellular pathogens as well as participate in the pathogenesis of the autoinmune diseases and in the development of delayed type hyper-sensitivity. In Th1 cells, the IL-2 increases the expression of T-bet and IL-12R㬢 which then promotes the sustainability of this phenotype (23).

Th2. A Th2 response is induced by extracellular pathogens and allergens. It is generated by the effect of the IL-4, IL-25, IL-33, and IL-11 secreted by mast cells, eosinophils, and NKT cells. These cytokines induce the intracellular activation of STAT-6 and GATA-3, which initiates the secretion of cytokines of the Th2 phenotype such as IL-4, IL-5, IL-9, IL-13, IL-10, and IL-25, as well as, the expression of CCR4 and ICOS (26, 27). Th2 cells induce immunoglobulin class switching to IgE, through a mechanism mediated by IL-4. The IgE, in turn, activates cells of the innate immune system such as basophils and mast cells and induces their degranulation and the liberation of histamin, heparin, proteases, serotonin, cytokines, and chemokines. These molecules generate contraction of the smooth muscle, increase vascular permeability, and recruit more inflammatory cells. Th2 cells also migrate to the lung and intestinal tissue where they recruit eosinophils (through the secretion of IL-5) and mast cells (through IL-9). This leads to tissue eosinophilia and hyperplasia of mast cells. When acting upon epithelial cells and the smooth muscle (through IL-4 and IL-13), the Th2 cells induce production of mucus, metaplasia of the Goblet cells, and airway hyper-responsiveness as observed in allergic diseases (26). In the Th2 cells, IL-2 induces the expression of IL-4Rα and keeps the loci of the IL-4 and IL-13 genes in an accessible configuration during the final stages of the differentiation of these cells, which helps to conserve this phenotype (23).

Th9. This subset of T-helper cells arises through the effect of TGF-β and IL-4. Th9 cells produce IL-9 and IL-10 and do not express cytokines or transcription factors of the Th1, Th2, or Th17 subsets (28). IL-9 promotes the growth of mast cells and the secretion of IL-1β, IL-6, IL-13, and TGF-β. Nevertheless, IL-9 is not exclusive to this cell subpopulation. It is also produced by Th2, Th17, Treg, mast cells, and NKT cells (29). In allergic processes and infections by helminthes, the IL-9 stimulates the liberation of mast cell products and, through IL-13 and IL-5, indirectly induces the production of mucus, eosinophilia, hyperplasia of the epithelium, and muscular contraction (30).

Th17. These cells are induced by the combined action of IL-6, IL-21, IL-23, and TGF-β. The IL-6 activates the naïve T Cell resulting in the autocrine production of IL-21 which in synergy with TGF-β induces the nuclear transcription factor (ROR)c and the production of IL-17A and IL-17F. IL-23 is essential for the survival and activation of Th17 after its differentiation and selectively regulates the expression of IL-17 (31).

The Th17 cells are mainly located in the pulmonary and digestive mucosa. They produce IL-17A, IL-17F, IL-6, IL-9, IL-21, IL-22, TNF-α, and CCL20. IL-17, in synergy with TNF-α, promotes the expression of genes that amplify the inflammatory process. IL-17 binds to its receptor in mesenchymatous cells such as fibroblasts, epithelial cells, and endothelial cells to promote the liberation of chemokines and inflammation mediators such as IL-8, MCP-1, G-CSF, and GM-CSF (31). IL-17 and IL-22 also induce the production of defensins. The inflammatory environment generated by Th17 cells is associated with diseases that have an important inflammatory component such as rheumatoid arthritis, systemic lupus erythematosus (SLE), bronchial asthma, and transplant rejection (32).

Th22.This T Cell subset is generated by the combined action of the IL-6 and TNF-α with the participation of plasmacytoid DC. Th22 cells are characterized by the secretion of IL-22 and TNF-α. The transcripcional profile of these cells also includes genes that encode for FGF (fibroblast growth factor), IL-13, and chemokines implicated in angiogenesis and fibrosis. The main transcription factor associated with this phenotype is AHR. In the skin, IL-22 induces antimicrobial peptides, promotes the proliferation of keratinocytes, and inhibits their differentiation which suggests a role in the scarring of wounds and in natural defence mechanisms (33). The Th22 cells express CCR4, CCR6, and CCR10 which allows them to infiltrate the epidermis in individuals with inflammatory skin disorders. They participate in Crohn’s disease, psoriasis, and the scarring of wounds (34).

Follicular helper T Cells (Tfh). These cells were discovered just over a decade ago as germinal center T Cells that help B Cells to produce antibodies. The development of these cells depends on IL-6, IL-12, and IL-21. They are characterized by the sustained expression of CXCR5 and the loss of CCR7, which allows Tfh cells to relocate from the T Cell zone to the B Cell follicles that express CXCL13. There, they induce the formation of germinal centers, the transformation of B Cells into plasma cells, the production of antibodies with different isotypes, and the production of memory B Cells (35).

Among all the T-helper cell subsets, the Tfh express the TCR with the highest affinity for Ag and the greatest quantity of costimulatory molecules such as ICOS and CD40L. Furthermore, they express the transcription factor BCL-6 and cytokines such as IL-21, IL-4, and IL-10 which induce the differentiation of B Cells and the production of Ab (35).

Regulatory T Cells (Treg). Regulatory T Cells represent 5% to 10% of CD4+ T Cells in healthy adults. They constitutively express markers of activation such as CTLA-4 (CD152), α receptor of IL-2 (CD25), OX-40, and L-selectin (36). These are considered anergic in the absense of IL-2 which makes them dependent on the IL-2 secreted by other cells. By their mechanism of action and origin, they represent a heterogenous population of cells that can be divided into two: natural Treg cells of thymic origin and induced Treg cells differentiated on the periphery (37).

The natural Treg cells are CD4 + CD25 high and constitutively express the transcription factor FOXP3 + which is essential for their development. The CD4 + CD25 − FOXP3 − cells can differentiate into Treg cells in the presence of IL-10 and TGF-β and for interaction with immature DC. In contrast, the differentiation of Treg cells is inhibited when mature DC produces IL-6.

The production of Treg cells is essential in preventing autoimmune diseases and avoiding prolonged immunopathological processes and allergies. They are also essential for inducing tolerance to allogenic transplants as well as tolerance of the foetus during pregnancy. They supress the activation, proliferation, and effector function of a wide range of immune cells including autoreactive CD4 or CD8 T Cells which escape negative selection in the thymus, NK cells, NKT, LB, and APC. Like a double-edged sword, Treg cells also supress antitumoral responses, which favors tumor development (37).

Action mechanisms of Treg cells are depicted in Figure 5. These mechanisms can be broadly divided into those that target T Cells (regulatory cytokines, IL-2 consumption, and cytolysis) and those that primarily target APCs (decreased costimulation or decreased antigen presentation). Major mechanisms by which Treg cells exert their functions include (36, 38):

Figure 5

Mechanisms of action of T regulatory cells. Abbreviations. TGFβ: Transforming growth factor beta, CTLA4: cytotoxic T-lymphocyte antigen 4.


T cell

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T cell, also called T lymphocyte, type of leukocyte (white blood cell) that is an essential part of the immune system. T cells are one of two primary types of lymphocytes—B cells being the second type—that determine the specificity of immune response to antigens (foreign substances) in the body.

T cells originate in the bone marrow and mature in the thymus. In the thymus, T cells multiply and differentiate into helper, regulatory, or cytotoxic T cells or become memory T cells. They are then sent to peripheral tissues or circulate in the blood or lymphatic system. Once stimulated by the appropriate antigen, helper T cells secrete chemical messengers called cytokines, which stimulate the differentiation of B cells into plasma cells (antibody-producing cells). Regulatory T cells act to control immune reactions, hence their name. Cytotoxic T cells, which are activated by various cytokines, bind to and kill infected cells and cancer cells.

Because the body contains millions of T and B cells, many of which carry unique receptors, it can respond to virtually any antigen.

The Editors of Encyclopaedia Britannica This article was most recently revised and updated by Adam Augustyn, Managing Editor, Reference Content.


T cell types

Naïve T lymphocytes are cells that have not yet encountered their specific antigen. In peripheral lymphoid organs, naïve T lymphocytes can interact with antigen-presenting cells (APCs), which use MHC molecules to present antigen. Once the T lymphocytes recognise their specific antigens, they proliferate and differentiate into one of several effector T lymphocyte subsets. Effector T lymphocytes interact with host cells (rather than the pathogen) to carry out their immune function.

T lymphocytes use co-receptors to bind to the MHC molecules. Co-receptors can be either CD4 or CD8. CD proteins help to differentiate major groups of effector T lymphocytes. Naïve CD8+ T lymphocytes will become cytotoxic T lymphocytes. Alternatively, CD4+ T lymphocytes will become T helper lymphocytes, each of which specialised for particular tasks.

Cytotoxic T cells

Cytotoxic T lymphocytes kill their target cells primarily by releasing cytotoxic granules into the target cell. These cells recognise their specific antigen (such as fragments of viruses) only when presented on MHC Class I molecules present on the surface of all nucleated cells.

MHC Class I molecules interact with CD8 on the cytotoxic T cells. Cytotoxic T cells require several signals from other cells like dendritic cells and T helper cells to be activated.

Their main function is to kill virally infected cells, but they also kill cells with intracellular bacteria or tumorous cells.

T-Helper Lymphocytes

T helper cells (Th) have a wide range of effector functions and can differentiate into many different subtypes, such as Th1, Th2, Th17, TfH cells and regulatory T cells.

They become activated when they are presented with peptide antigens on MHC Class II molecules. These are expressed on the surface of APCs. MHC Class II molecules interact with CD4 on the T helper cells, which helps identify this cell type.

CD4+ T cell functions include activating other immune cells, releasing cytokines, and helping B cells to produce antibodies. They help to shape, activate and regulate the adaptive immune response.

Memory T cells

Antigen-specific, long-lived memory T lymphocytes form following an infection. Memory T lymphocytes are important because they can quickly proliferate into large numbers of effector T lymphocyte upon re-exposure to the antigen and have a low threshold for activation.

They provide the immune system with memory against previously encountered antigens. Memory T lymphocytes may either be CD4+ or CD8+.

[caption align="aligncenter"] Fig 2 - Diagram summarising T cell activation.[/caption]

18.3: T Lymphocytes - Biology

1 Phagocytes and lymphocytes are the cells of the immune system.

2 The diagram shows how to recognise phagocytes and lymphocytes in microscope slides and photomicrographs of blood.



3 Phagocytes originate in the bone marrow and are produced there throughout life. There are two types: neutrophils that circulate in the blood and enter infected tissues, and macrophages that remain inside tissues. They both destroy bacteria and viruses by phagocytosis.

4 Antigens are ‘foreign’ (non-self) macromolecules that stimulate the immune system.

5 Lymphocytes also originate in bone marrow. There are two types: B-lymphocytes (B cells) and T-lymphocytes (T cells). As they mature, B cells and T cells gain glycoprotein receptors that are specific to each cell. Each cell divides to form a small clone of cells that spreads throughout the body in the blood and in the lymphoid tissue (e.g. lymph nodes and spleen).

6 B cells mature in bone marrow. T cells mature in the thymus gland. During maturation, many T cells are destroyed, as they express receptors that interact with self-antigens. If left to circulate in the body, they would destroy cells and tissues. The T cells that are not destroyed recognise non-self antigens, such as those on the surfaces of pathogens.

7 During an immune response, those B and T cells that have receptors specific to the antigen are
activated.

8 When B cells are activated they form plasma cells which secrete antibodies.

9 T cells do not secrete antibodies their surface receptors are similar to antibodies and identify
antigens. They develop into either T helper cells or killer T cells (cytotoxic T cells). T helper cells
secrete cytokines that control the immune system, activating B cells and killer T cells, which kill
infected host cells.

10 During an immune response, memory cells are formed which retain the ability to divide rapidly and develop into active B or T cells on a second exposure to the same antigen (immunological memory). The diagram on the next page summarises the actions of B cells and T cells during an immune response.

11 Antibodies are globular glycoproteins. They all have one or more pairs of identical heavy polypeptides and of identical light polypeptides. Each type of antibody interacts with one antigen via the specific shape of its variable region. Each molecule of the simplest antibody (IgG) can bind to two antigen molecules. Larger antibodies (IgM and IgA) have more than two antigen-binding sites.

12 Antibodies agglutinate bacteria, prevent viruses infecting cells, coat bacteria and viruses to aid
phagocytosis, act with plasma proteins to burst bacteria, and neutralise toxins.

13 Active immunity is the production of antibodies and active T cells during a primary immune response to an antigen acquired either naturally by infection or artifi cially by vaccination. This gives permanent immunity.

14 Passive immunity is the introduction of antibodies either naturally across the placenta or in breast milk, or artifi cially by injection. This gives temporary immunity.

15 Vaccination confers artificial active immunity by introducing a small quantity of an antigen by
injection or by mouth. This may be a whole living organism, a dead one, a harmless version of a toxin (toxoid) or a preparation of antigens.

2 What is the function of plasma cells during an immune response?

A to become memory cells
B to ingest invading bacteria
C to kill cells infected with viruses
D to secrete antibodies


5 Newborn babies acquire immunity from their mothers.
Why is this immunity only temporary?

A no memory cells are produced by the baby
B not enough antibodies are produced
C the antibodies act only in the mother
D the immunity is not inherited

6 The statements describe molecular structure.
1 an insoluble fibrous glycoprotein
2 has quaternary structure held together by disulfide bonds
3 has two identical binding sites
4 made up of two longer and two shorter chains

Which statements describe an antibody molecule?
A 1, 2, 3 and 4
B 1, 2 and 3 only
C 2, 3 and 4 only
D 3 and 4 only

7 An individual’s immunity may result from:
1 having memory cells after an infection
2 having memory cells after being injected with dead bacteria
3 being injected with antibodies
4 receiving antibodies from breast milk.

Which row shows an example of the different types of immunity?
























9 The statements are about the role of a phagocyte.
1 bacteria in phagocytic vacuole
2 hydrolysis of bacteria
3 phagocyte attracted to bacteria
4 bacteria taken into phagocyte by endocytosis
5 fusion of lysosomes with phagocytic vacuole

Which of the following shows the sequence of events after antibodies have become attached to a pathogenic bacterium?
A 1 → 5 → 2 → 3 → 4
B 3 → 4 → 1 → 5 → 2
C 4 → 1 → 3 → 5 → 2
D 5 → 2 → 3 → 4 → 1

10 The statements describe lymphocytes.
1 Each B-lymphocyte can make only one type of antibody.
2 Both B-lymphocytes and T-lymphocytes circulate in the blood and lymph.
3 Some T-lymphocytes stimulate B-lymphocytes to divide.
4 B-lymphocytes can develop into plasma cells and secrete antibodies.
5 Some T-lymphocytes kill any of the body’s cells that are infected with pathogens.

Which statements are correct?
A 1, 2, 3, 4 and 5
B 1, 2, 3 and 4 only
C 2, 3 and 4 only
D 3, 4 and 5 only

Answers to Multiple choice test

1 C
2 D
3 D
4 A

Exam-style questions

5 a i bone marrow [1]
ii mitosis [1]
iii plasma cell [1]
iv antibody [1]

b i antigen refers to any substance that stimulates the production of antibodies antibodies are proteins produced by, plasma cells/(activated) B-lymphocytes each antibody is specific to an antigen [3]
ii self refers to antigen(s) within a person’s body (e.g. those of the ABO blood group system which they have) all the antigens that the immune system does not recognise as foreign [max. 1]

non-self refers to antigen(s) that are not in a person’s body (e.g. those of, pathogens/the ABO system, that they do not have) all the antigens that the immune system recognises as foreign [max. 1]

c memory cell
remains in circulation/lymph system/body
is specific to an antigen on tetanus bacteria
responds quickly to another infection by (same strain of) pathogen
as there are a large number/is a large clone
during (secondary/subsequent) immune response
differentiate into plasma cells
to give large number of antibody molecules in short space of time [max. 3]


6 a phagocyte has lobed nucleus
lysosomes
larger quantity of cytoplasm [3]
Reject statement that phagocyte is larger, as question asks for diff erences in structure, not size.

b presentation of antigen(s) by macrophages/other APCs
some T-lymphocytes have receptors complementary to antigen
these are selected
divide by mitosis
helper T cells secrete cytokines
to activate B-lymphocytes
to secrete antibodies
killer T cells search for cells infected by, parasite/ pathogen
destroy host cell (and pathogen)
prevent reproduction of pathogen [max. 6]

c B-lymphocytes can be activated by presence of, antigen/pathogen alone
without involvement of macrophages
B-lymphocytes diff erentiate into plasma cells
secrete antibodies (T cells do not secrete antibodies) [max. 2]



7 a i immunity is gained by the transfer of antibodies from another source
no immune response within the body
antigen(s)/pathogen(s),
have not entered the body [max. 2]

ii natural passive immunity: antibodies cross the placenta
in breast milk/colostrum [max. 1]

b i baby has passive immunity
antibodies against measles antigens (from mother) will interact with measles viruses/ antigens in vaccine
so prevent an immune response
therefore no memory cells will be formed [max. 3]

ii difficulty with timing first vaccination
many children are not vaccinated at appropriate time
measles is highly infectious
vaccination programmes concentrated on other infectious diseases which have more severe effect, such as smallpox and polio [max. 3]

c herd/mass vaccination/immunity
prevented spread through population
surveillance for infected people
very easy to identify infected people/no symptomless carriers
contact tracing to fi nd people who may have become infected ring vaccination/vaccination of all people in surrounding area
prevented spread from isolated infected people
one dose of the vaccine was enough to give lifelong immunity/no boosters required
vaccine contained ‘live’ virus
smallpox virus was stable/did not mutate
no antigenic variation
same vaccine was used for whole programme/did not need to be changed heat-stable/freeze-dried, vaccine
suitable for hot countries/isolated areas/rural areas
bifurcated/steel, needle made vaccinating easy
did not need to be done by health professionals [max. 6]


8 a transcription (of DNA)
translation (of RNA)
assembly of amino acids to make four polypeptides
assembly of polypeptides to make antibody molecule
packaged in Golgi body into vesicles
exocytosis [max. 4]

b i X = variable region/antigen-binding site Y = constant region [2]
ii disulfide [1]

c variable region(s) are antigen-binding sites
variable regions, are specific/complementary, to antigen
variable region has diff erent amino acid sequences for diff erent antigens
20 different amino acids can be arranged to form diff erent shapes
disulfide bonds hold polypeptides together
hinge region allows flexibility in binding to antigen
constant region for binding to receptors on phagocytes [max. 4]


17.3 Adaptive Immunity

The adaptive, or acquired, immune response takes days or even weeks to become established—much longer than the innate response however, adaptive immunity is more specific to an invading pathogen. Adaptive immunity is an immunity that occurs after exposure to an antigen either from a pathogen or a vaccination. An antigen is a molecule that stimulates a response in the immune system. This part of the immune system is activated when the innate immune response is insufficient to control an infection. In fact, without information from the innate immune system, the adaptive response could not be mobilized. There are two types of adaptive responses: the cell-mediated immune response , which is controlled by activated T cells , and the humoral immune response , which is controlled by activated B cells and antibodies. Activated T and B cells whose surface binding sites are specific to the molecules on the pathogen greatly increase in numbers and attack the invading pathogen. Their attack can kill pathogens directly or they can secrete antibodies that enhance the phagocytosis of pathogens and disrupt the infection. Adaptive immunity also involves a memory to give the host long-term protection from reinfection with the same type of pathogen on reexposure, this host memory will facilitate a rapid and powerful response.

B and T Cells

Lymphocytes, which are white blood cells, are formed with other blood cells in the red bone marrow found in many flat bones, such as the shoulder or pelvic bones. The two types of lymphocytes of the adaptive immune response are B and T cells (Figure 17.12). Whether an immature lymphocyte becomes a B cell or T cell depends on where in the body it matures. The B cells remain in the bone marrow to mature (hence the name “B” for “bone marrow”), while T cells migrate to the thymus, where they mature (hence the name “T” for “thymus”).

Maturation of a B or T cell involves becoming immunocompetent, meaning that it can recognize, by binding, a specific molecule or antigen (discussed below). During the maturation process, B and T cells that bind too strongly to the body’s own cells are eliminated in order to minimize an immune response against the body’s own tissues. Those cells that react weakly to the body’s own cells, but have highly specific receptors on their cell surfaces that allow them to recognize a foreign molecule, or antigen, remain. This process occurs during fetal development and continues throughout life. The specificity of this receptor is determined by the genetics of the individual and is present before a foreign molecule is introduced to the body or encountered. Thus, it is genetics and not experience that initially provides a vast array of cells, each capable of binding to a different specific foreign molecule. Once they are immunocompetent, the T and B cells will migrate to the spleen and lymph nodes where they will remain until they are called on during an infection. B cells are involved in the humoral immune response, which targets pathogens loose in blood and lymph, and T cells are involved in the cell-mediated immune response, which targets infected cells.

Humoral Immune Response

As mentioned, an antigen is a molecule that stimulates a response in the immune system. Not every molecule is antigenic. B cells participate in a chemical response to antigens present in the body by producing specific antibodies that circulate throughout the body and bind with the antigen whenever it is encountered. This is known as the humoral immune response. As discussed, during maturation of B cells, a set of highly specific B cells are produced that have many antigen receptor molecules in their membrane (Figure 17.13).

Each B cell has only one kind of antigen receptor, which makes every B cell different. Once the B cells mature in the bone marrow, they migrate to lymph nodes or other lymphatic organs. When a B cell encounters the antigen that binds to its receptor, the antigen molecule is brought into the cell by endocytosis and reappears on the surface of the cell bound to an MHC class II molecule . When this process is complete, the B cell is sensitized. In most cases, the sensitized B cell must then encounter a specific kind of T cell, called a helper T cell, before it is activated. The helper T cell must already have been activated through an encounter with the antigen (discussed below).

The helper T cell binds to the antigen-MHC class II complex and is induced to release cytokines that induce the B cell to divide rapidly, which makes thousands of identical (clonal) cells. These daughter cells become either plasma cells or memory B cells. The memory B cells remain inactive at this point, until another later encounter with the antigen, caused by a reinfection by the same bacteria or virus, results in them dividing into a new population of plasma cells. The plasma cells, on the other hand, produce and secrete large quantities, up to 100 million molecules per hour, of antibody molecules. An antibody , also known as an immunoglobulin (Ig), is a protein that is produced by plasma cells after stimulation by an antigen. Antibodies are the agents of humoral immunity. Antibodies occur in the blood, in gastric and mucus secretions, and in breast milk. Antibodies in these bodily fluids can bind pathogens and mark them for destruction by phagocytes before they can infect cells.

These antibodies circulate in the blood stream and lymphatic system and bind with the antigen whenever it is encountered. The binding can fight infection in several ways. Antibodies can bind to viruses or bacteria and interfere with the chemical interactions required for them to infect or bind to other cells. The antibodies may create bridges between different particles containing antigenic sites clumping them all together and preventing their proper functioning. The antigen-antibody complex stimulates the complement system described previously, destroying the cell bearing the antigen. Phagocytic cells, such as those already described, are attracted by the antigen-antibody complexes, and phagocytosis is enhanced when the complexes are present. Finally, antibodies stimulate inflammation, and their presence in mucus and on the skin prevents pathogen attack.

Antibodies coat extracellular pathogens and neutralize them by blocking key sites on the pathogen that enhance their infectivity (such as receptors that “dock” pathogens on host cells) (Figure 17.14). Antibody neutralization can prevent pathogens from entering and infecting host cells. The neutralized antibody-coated pathogens can then be filtered by the spleen and eliminated in urine or feces.

Antibodies also mark pathogens for destruction by phagocytic cells, such as macrophages or neutrophils, in a process called opsonization. In a process called complement fixation, some antibodies provide a place for complement proteins to bind. The combination of antibodies and complement promotes rapid clearing of pathogens.

The production of antibodies by plasma cells in response to an antigen is called active immunity and describes the host’s active response of the immune system to an infection or to a vaccination. There is also a passive immune response where antibodies come from an outside source, instead of the individual’s own plasma cells, and are introduced into the host. For example, antibodies circulating in a pregnant woman’s body move across the placenta into the developing fetus. The child benefits from the presence of these antibodies for up to several months after birth. In addition, a passive immune response is possible by injecting antibodies into an individual in the form of an antivenom to a snake-bite toxin or antibodies in blood serum to help fight a hepatitis infection. This gives immediate protection since the body does not need the time required to mount its own response.

Cell-Mediated Immunity

Unlike B cells, T lymphocytes are unable to recognize pathogens without assistance. Instead, dendritic cells and macrophages first engulf and digest pathogens into hundreds or thousands of antigens. Then, an antigen-presenting cell (APC) detects, engulfs, and informs the adaptive immune response about an infection. When a pathogen is detected, these APCs will engulf and break it down through phagocytosis. Antigen fragments will then be transported to the surface of the APC, where they will serve as an indicator to other immune cells. A dendritic cell is an immune cell that mops up antigenic materials in its surroundings and presents them on its surface. Dendritic cells are located in the skin, the linings of the nose, lungs, stomach, and intestines. These positions are ideal locations to encounter invading pathogens. Once they are activated by pathogens and mature to become APCs they migrate to the spleen or a lymph node. Macrophages also function as APCs. After phagocytosis by a macrophage, the phagocytic vesicle fuses with an intracellular lysosome. Within the resulting phagolysosome, the components are broken down into fragments the fragments are then loaded onto MHC class II molecules and are transported to the cell surface for antigen presentation (Figure 17.15). Helper T cells cannot properly respond to an antigen unless it is processed and embedded in an MHC class II molecule. The APCs express MHC class II on their surfaces, and when combined with a foreign antigen, these complexes signal an invader.

Concepts in Action

View this animation from Rockefeller University to see how dendritic cells act as sentinels in the body’s immune system.

T cells have many functions. Some respond to APCs of the innate immune system and indirectly induce immune responses by releasing cytokines. Others stimulate B cells to start the humoral response as described previously. Another type of T cell detects APC signals and directly kills the infected cells, while some are involved in suppressing inappropriate immune reactions to harmless or “self” antigens.

There are two main types of T cells: helper T lymphocytes (TH) and the cytotoxic T lymphocytes (TC). The TH lymphocytes function indirectly to tell other immune cells about potential pathogens. TH lymphocytes recognize specific antigens presented by the MHC class II complexes of APCs. There are two populations of TH cells: TH1 and TH2. TH1 cells secrete cytokines to enhance the activities of macrophages and other T cells. TH2 cells stimulate naïve B cells to secrete antibodies. Whether a TH1 or a TH2 immune response develops depends on the specific types of cytokines secreted by cells of the innate immune system, which in turn depends on the nature of the invading pathogen.

Cytotoxic T cells (TC) are the key component of the cell-mediated part of the adaptive immune system and attack and destroy infected cells. TC cells are particularly important in protecting against viral infections this is because viruses replicate within cells where they are shielded from extracellular contact with circulating antibodies. Once activated, the TC creates a large clone of cells with one specific set of cell-surface receptors, as in the case with proliferation of activated B cells. As with B cells, the clone includes active TC cells and inactive memory TC cells. The resulting active TC cells then identify infected host cells. Because of the time required to generate a population of clonal T and B cells, there is a delay in the adaptive immune response compared to the innate immune response.

TC cells attempt to identify and destroy infected cells before the pathogen can replicate and escape, thereby halting the progression of intracellular infections. TC cells also support NK lymphocytes to destroy early cancers. Cytokines secreted by the TH1 response that stimulates macrophages also stimulate TC cells and enhance their ability to identify and destroy infected cells and tumors. A summary of how the humoral and cell-mediated immune responses are activated appears in Figure 17.16.

B plasma cells and TC cells are collectively called effector cells because they are involved in “effecting” (bringing about) the immune response of killing pathogens and infected host cells.

Immunological Memory

The adaptive immune system has a memory component that allows for a rapid and large response upon reinvasion of the same pathogen. During the adaptive immune response to a pathogen that has not been encountered before, known as the primary immune response , plasma cells secreting antibodies and differentiated T cells increase, then plateau over time. As B and T cells mature into effector cells, a subset of the naïve populations differentiates into B and T memory cells with the same antigen specificities (Figure 17.17). A memory cell is an antigen-specific B or T lymphocyte that does not differentiate into an effector cell during the primary immune response, but that can immediately become an effector cell on reexposure to the same pathogen. As the infection is cleared and pathogenic stimuli subside, the effectors are no longer needed and they undergo apoptosis. In contrast, the memory cells persist in the circulation.

Visual Connection

The Rh antigen is found on Rh-positive red blood cells. An Rh-negative female can usually carry an Rh-positive fetus to term without difficulty. However, if she has a second Rh-positive fetus, her body may launch an immune attack that causes hemolytic disease of the newborn. Why do you think hemolytic disease is only a problem during the second or subsequent pregnancies?

If the pathogen is never encountered again during the individual’s lifetime, B and T memory cells will circulate for a few years or even several decades and will gradually die off, having never functioned as effector cells. However, if the host is re-exposed to the same pathogen type, circulating memory cells will immediately differentiate into plasma cells and TC cells without input from APCs or TH cells. This is known as the secondary immune response . One reason why the adaptive immune response is delayed is because it takes time for naïve B and T cells with the appropriate antigen specificities to be identified, activated, and proliferate. On reinfection, this step is skipped, and the result is a more rapid production of immune defenses. Memory B cells that differentiate into plasma cells output tens to hundreds-fold greater antibody amounts than were secreted during the primary response (Figure 17.18). This rapid and dramatic antibody response may stop the infection before it can even become established, and the individual may not realize they had been exposed.

Vaccination is based on the knowledge that exposure to noninfectious antigens, derived from known pathogens, generates a mild primary immune response. The immune response to vaccination may not be perceived by the host as illness but still confers immune memory. When exposed to the corresponding pathogen to which an individual was vaccinated, the reaction is similar to a secondary exposure. Because each reinfection generates more memory cells and increased resistance to the pathogen, some vaccine courses involve one or more booster vaccinations to mimic repeat exposures.

The Lymphatic System

Lymph is the watery fluid that bathes tissues and organs and contains protective white blood cells but does not contain erythrocytes. Lymph moves about the body through the lymphatic system, which is made up of vessels, lymph ducts, lymph glands, and organs, such as tonsils, adenoids, thymus, and spleen.

Although the immune system is characterized by circulating cells throughout the body, the regulation, maturation, and intercommunication of immune factors occur at specific sites. The blood circulates immune cells, proteins, and other factors through the body. Approximately 0.1 percent of all cells in the blood are leukocytes, which include monocytes (the precursor of macrophages) and lymphocytes. Most cells in the blood are red blood cells. Cells of the immune system can travel between the distinct lymphatic and blood circulatory systems, which are separated by interstitial space, by a process called extravasation (passing through to surrounding tissue).

Recall that cells of the immune system originate from stem cells in the bone marrow. B cell maturation occurs in the bone marrow, whereas progenitor cells migrate from the bone marrow and develop and mature into naïve T cells in the organ called the thymus.

On maturation, T and B lymphocytes circulate to various destinations. Lymph nodes scattered throughout the body house large populations of T and B cells, dendritic cells, and macrophages (Figure 17.19). Lymph gathers antigens as it drains from tissues. These antigens then are filtered through lymph nodes before the lymph is returned to circulation. APCs in the lymph nodes capture and process antigens and inform nearby lymphocytes about potential pathogens.

The spleen houses B and T cells, macrophages, dendritic cells, and NK cells (Figure 17.20). The spleen is the site where APCs that have trapped foreign particles in the blood can communicate with lymphocytes. Antibodies are synthesized and secreted by activated plasma cells in the spleen, and the spleen filters foreign substances and antibody-complexed pathogens from the blood. Functionally, the spleen is to the blood as lymph nodes are to the lymph.

Mucosal Immune System

The innate and adaptive immune responses compose the systemic immune system (affecting the whole body), which is distinct from the mucosal immune system. Mucosa associated lymphoid tissue (MALT) is a crucial component of a functional immune system because mucosal surfaces, such as the nasal passages, are the first tissues onto which inhaled or ingested pathogens are deposited. The mucosal tissue includes the mouth, pharynx, and esophagus, and the gastrointestinal, respiratory, and urogenital tracts.

Mucosal immunity is formed by MALT, which functions independently of the systemic immune system, and which has its own innate and adaptive components. MALT is a collection of lymphatic tissue that combines with epithelial tissue lining the mucosa throughout the body. This tissue functions as the immune barrier and response in areas of the body with direct contact to the external environment. The systemic and mucosal immune systems use many of the same cell types. Foreign particles that make their way to MALT are taken up by absorptive epithelial cells and delivered to APCs located directly below the mucosal tissue. APCs of the mucosal immune system are primarily dendritic cells, with B cells and macrophages having minor roles. Processed antigens displayed on APCs are detected by T cells in the MALT and at the tonsils, adenoids, appendix, or the mesenteric lymph nodes of the intestine. Activated T cells then migrate through the lymphatic system and into the circulatory system to mucosal sites of infection.

Immune Tolerance

The immune system has to be regulated to prevent wasteful, unnecessary responses to harmless substances, and more importantly, so that it does not attack “self.” The acquired ability to prevent an unnecessary or harmful immune response to a detected foreign substance known not to cause disease, or self-antigens, is described as immune tolerance . The primary mechanism for developing immune tolerance to self-antigens occurs during the selection for weakly self-binding cells during T and B lymphocyte maturation. There are populations of T cells that suppress the immune response to self-antigens and that suppress the immune response after the infection has cleared to minimize host cell damage induced by inflammation and cell lysis. Immune tolerance is especially well developed in the mucosa of the upper digestive system because of the tremendous number of foreign substances (such as food proteins) that APCs of the oral cavity, pharynx, and gastrointestinal mucosa encounter. Immune tolerance is brought about by specialized APCs in the liver, lymph nodes, small intestine, and lung that present harmless antigens to a diverse population of regulatory T (Treg) cells, specialized lymphocytes that suppress local inflammation and inhibit the secretion of stimulatory immune factors. The combined result of Treg cells is to prevent immunologic activation and inflammation in undesired tissue compartments and to allow the immune system to focus on pathogens instead.


Immunological Memory Is Due to Both Clonal Expansion and Lymphocyte Differentiation

The adaptive immune system, like the nervous system, can remember prior experiences. This is why we develop lifelong immunity to many common infectious diseases after our initial exposure to the pathogen, and it is why vaccination works. The same phenomenon can be demonstrated in experimental animals. If an animal is immunized once with antigen A, an immune response (either antibody or cell-mediated) appears after several days, rises rapidly and exponentially, and then, more gradually, declines. This is the characteristic course of a primary immune response, occurring on an animal's first exposure to an antigen. If, after some weeks, months, or even years have elapsed, the animal is reinjected with antigen A, it will usually produce a secondary immune response that is very different from the primary response: the lag period is shorter, and the response is greater. These differences indicate that the animal has “remembered” its first exposure to antigen A. If the animal is given a different antigen (for example, antigen B) instead of a second injection of antigen A, the response is typical of a primary, and not a secondary, immune response. The secondary response must therefore reflect antigen-specific immunological memory for antigen A (Figure 24-10).

Figure 24-10

Primary and secondary antibody responses. The secondary response induced by a second exposure to antigen A is faster and greater than the primary response and is specific for A, indicating that the adaptive immune system has specifically remembered encountering (more. )

The clonal selection theory provides a useful conceptual framework for understanding the cellular basis of immunological memory. In an adult animal, the peripheral lymphoid organs contain a mixture of cells in at least three stages of maturation: naïve cells, effector cells and memory cells. When naïve cells encounter antigen for the first time, some of them are stimulated to proliferate and differentiate into effector cells, which are actively engaged in making a response (effector B cells secrete antibody, while effector T cells kill infected cells or help other cells fight the infection). Instead of becoming effector cells, some naïve cells are stimulated to multiply and differentiate into memory cells�lls that are not themselves engaged in a response but are more easily and more quickly induced to become effector cells by a later encounter with the same antigen. Memory cells, like naïve cells, give rise to either effector cells or more memory cells (Figure 24-11).

Figure 24-11

A model for the cellular basis of immunological memory. When naïve lymphocytes are stimulated by their specific antigen, they proliferate and differentiate. Most become effector cells which function and then die, while others become long-lived (more. )

Thus, immunological memory is generated during the primary response in part because the proliferation of antigen-stimulated naïve cells creates many memory cells𠅊 process known as clonal expansion𠅊nd in part because memory cells are able to respond more sensitively and rapidly to the same antigen than do naïve cells. And, unlike most effector cells, which die within days or weeks, memory cells can live for the lifetime of the animal, thereby providing lifelong immunological memory.


Αβ and γδ T cell receptors: Similar but different

Anna Morath and Wolfgang A. Schamel, Schänzlestrasse 18, 79104 Freiburg, Germany.

Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany

Institute of Biology III, Faculty of Biology, University of Freiburg, Freiburg, Germany

Center for Chronic Immunodeficiency (CCI), Medical Center Freiburg and Faculty of Medicine, University of Freiburg, Freiburg, Germany

Anna Morath and Wolfgang A. Schamel, Schänzlestrasse 18, 79104 Freiburg, Germany.

Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany

Institute of Biology III, Faculty of Biology, University of Freiburg, Freiburg, Germany

Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany

Anna Morath and Wolfgang A. Schamel, Schänzlestrasse 18, 79104 Freiburg, Germany.

Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany

Institute of Biology III, Faculty of Biology, University of Freiburg, Freiburg, Germany

Center for Chronic Immunodeficiency (CCI), Medical Center Freiburg and Faculty of Medicine, University of Freiburg, Freiburg, Germany

Anna Morath and Wolfgang A. Schamel, Schänzlestrasse 18, 79104 Freiburg, Germany.

Abstract

There are 2 populations of T lymphocytes, αβ T and γδ T cells, that can be distinguished by the expression of either an αβ TCR or a γδ TCR, respectively. Pairing of the Ag binding heterodimer, which consists of TCR-α/TCR-β (TCRαβ) or TCR-γ/TCR-δ (TCRγδ), with proteins of the CD3 complex forms the complete αβ or γδ TCR. Despite some similarities in the structure of TCRαβ and TCRγδ and the shared subunits of the CD3 complex, the 2 receptors differ in important aspects. These include the assembly geometry of the complex, the glycosylation pattern, the plasma membrane organization, as well as the accessibility of signaling motifs in the CD3 intracellular tails. These differences are reflected in the different demands and outcomes of ligand-induced signaling. It was shown that exposure of the proline-rich sequence (PRS) in CD3ε occurs with all activating αβ TCR ligands and is required to induce αβ TCR signaling. In sharp contrast, CD3ε PRS exposure was not induced by binding of those ligands to the γδ TCR that have been studied. Further, signaling by the γδ TCR occurs independently of CD3ε PRS exposure. Interestingly, it can be enhanced by anti-CD3ε Ab-induced enforcement of CD3ε PRS exposure. This review contrasts these two similar, but different immune receptors.


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