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12.3C: T4-Lymphocytes (T4-Cells)

Skills to Develop

  1. Describe the overall function of T4-lymphocytes and their activation in terms of the following:
    1. the role of their TCRs and CD4 molecules
    2. what they recognize on antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B-lymphocytes.
    3. the role of antigen-presenting dendritic cells in the activation of naive T4-lymphocytes.
  2. Compare TH1, TH2, TH17, Treg, and TFH lymphocytes in terms of their primary function(s) in immunity.

The primary role of T4-lymphocytes (T4-Helper Cells, CD4+ Cells) is to regulate the body's immune responses. Once naive T4-lymphocytes are activated by dendritic cells, they proliferate and differentiate into T4-effector lymphocytes that regulate the immune responses by way of the cytokines they produce.

T-lymphocytes are lymphocytes that are produced in the bone marrow, but require interaction with the thymus for their maturation. T4-lymphocytes are T-lymphocytes displaying a surface molecule called CD4 molecules. They also have on their surface, epitope receptors called T-cell receptors or TCRs that, in cooperation with the CD4 molecules, have a shape capable of recognizing peptides from exogenous antigens bound to MHC-II molecules on the surface of antigen-presenting cells (APCs) such as dendritic cells (Figure 1), macrophages (Figure 2), and B-lymphocytes (Figure 3). The TCR recognizes the peptide while the CD4 molecule recognizes the MHC-II molecule.

Figure 1: A T4-Lymphocyte Recognizing Epitope/MHC-II on an Antigen-Presenting Dendritic Cell. Exogenous antigens are those from outside cells of the body. Examples include bacteria, free viruses, yeasts, protozoa, and toxins. These exogenous antigens enter antigen-presenting dendritic cells through phagocytosis. The microbes are engulfed and placed in a phagosome. After lysosomes fuse with the phagosome, protein antigens are degraded by proteases into a series of peptides. These peptides eventually bind to grooves in MHC-II milecules and are transported to the surface of the APC. T4-lymphocytes are then able to recognize peptide/MHC-II complexes by means of their T-cell receptors (TCRs) and CD4 molecules.

During its development, each T4-lymphocyte becomes genetically programmed by gene-splicing reactions similar to those in B-lymphocytes, to produce a T-cell receptor or TCR with a unique specificity. Identical molecules of that TCR are placed on its surface where they are able to bind an epitope/MHC-II complex on an APC such as a dendritic cell, a macrophage, or a B-lymphocyte with a corresponding shape. It is estimated that the human body has the ability to recognize 107 or more different epitopes. In order to recognize this immense number of different epitopes, the body produces 107 or more distinct clones of T-lymphocytes, each with a unique T-cell receptor. In this variety of T-cell receptors there is bound to be at least one that has an epitope-binding site able to fit, at least to some degree, peptides of any antigen the immune system eventually encounters.

Figure 2: Activation of a Macrophage by a TH1 Lymphocyte. 1. Engulfed bacteria inside a phagosome or a phagolysosome. 2. An activated TH1 lymphocyte binds to a peptide/MHC-II complex on a macrophage by way of its TCR and CD4 molecule. Co-stimulatory molecules such as CD40L on the TH1 cell then bind toCD40 on a macrophage. 3. This triggers the TH1 lymphocyte to secrete the cytokine interferon-gamma (IFN-γ) that binds to IFN-γ receptors receptors on the macrophage. 4. The IFN-γ activates the macrophage enabling it to produce more hydrolytic lysosomal enzymes, nitric oxide, and toxic oxygen radicals that destroy the microorganisms within the phagosomes and phagolysosomes.

Activation of a naive T4-lymphocyte by a dendritic cell

Effector T4-lymphocytes are cells the body uses to regulate both humoral immunity and cell-mediated immunity through cytokine they produce. In order to do so, however, naive T4-lymphocytes must first become activated by dendritic cells. As mentioned under antigen-presenting cells, immature dendritic cells located under the surface epithelium of the skin and the surface epithelium of the mucous membranes, throughout the body's lymphoid tissues, and in most solid organs engulf exogenous antigens by receptor-mediated phagocytosis and by macropinocytosis. They then detach and enter the lymphoid system (Figure 4 and Figure 5 ). During this process, they mature and process protein antigens so that peptide epitopes can be bound to MHC-II molecules that are subsequently placed on the surface of the dendritic cell (Figure 6). Here they can present protein epitopes bound to MHC-II molecules to naive T4-lymphocytes.

Figure 6: Binding of Peptide Epitopes from Exogenous Antigens to MHC-II Molecules. Exogenous antigens are those from outside cells of the body. Examples include bacteria, free viruses, yeasts, protozoa, and toxins. These exogenous antigens enter antigen-presenting cells or APCs (macrophages, dendritic cells, and B-lymphocytes) through phagocytosis. The microbes are engulfed and placed in a phagosome. After lysosomes fuse with the phagosome, protein antigens are degraded by proteases into a series of peptides. These peptides eventually bind to grooves in MHC-II milecules and are transported to the surface of the APC. T4-lymphocytes are then able to recognize peptide/MHC-II complexes by means of their T-cell receptors (TCRs) and CD4 molecules.

Certain dendritic cells are capable of cross-presentation of endogenous antigens to naive T4-lymphocytes. In this way, T4-lymphocytes can play a role in defending against both exogenous and endogenous antigens. Naive T-4 lymphocytes circulate in the blood. In response to chemokines produced by lymphoid tissues, they leave the vascular endothelium in regions called high endothelial venules and enter lymph nodes (Figure 7) or other lymphoid tissues, a process called diapedesis.

Figure 7: Structure of a Lymph Nodes.Antigens enter lymph nodes through afferent lymphoid vessels. Antigen-presenting dendritic cells enter the lymph node through afferent lymphatic vessels while naive B-lymphocytes, and naive T-lymphocytes enter through high endothelial venules. Non-activated and effector lymphocytes leave the lymph node through efferent lymphatic vessels. Naive B-lymphocytes become activated, proliferate, and differentiate into plasma cells in the germinal centers of lymphoid follicles while naive T-lymphocytes become activated, proliferate and differentiate into T-effector lymphocytes in the T-cell area.

As naive T4-lymphocytes migrate through the cortical region of lymph nodes, they use surface cell adhesion molecules such as LFA-1 and CD2 to bind transiently to corresponding receptors such as ICAM-1, ICAM-2 and CD58 on the surface of dendritic cells. This transient binding allows time for the TCRs on the T4-lymphocyte to sample large numbers of MHC-II/peptide complexes on the antigen-presenting dendritic cells (Figure 8).

Figure 8: Transient binding of T4-Lymphocytes to Dendritic Cells.As naive T4-lymphocytes migrate through the cortical region of lymph nodes, they use surface cell adhesion molecules such as LFA-1 and CD2 to bind transiently to corresponding receptors such as ICAM-1, ICAM-2 and CD58 on the surface of dentritic cells. This transient binding allows time for the TCRs on the T8-lymphocyte to sample large numbers of MHC-II/peptide complexes on the antigen-presenting dendritic cells.

Those naive T4-lymphocytes not activated by epitopes of antigens on the dendritic cells exit the lymph node (or other lymphoid tissue) and eventually re-enter the bloodstream. However, if a TCR and CD4 molecule of the naive T4-lymphocyte detects a corresponding MHC-II/peptide complex on a mature dendritic cell, this will send a first signal for the activation of that naive T-lymphocyte. Next, a second signal that promotes survival of that T-lymphocyte is sent when co-stimulatory molecules such as B7.1 and B7.2 on the dendritic cell bind to CD28 molecules on the T4-lymphocyte. Finally, the dendritic cell produces cytokines such as interleukin-6 (IL-6), IL-4, IL-12, and T-cell growth factor-beta (TGF-ß) that contribute to proliferation of the T4-lymphocytes and their differentiation into effector T4-lymphocytes, the cells the body uses to regulate both humoral immunity and cell-mediated immunity through the cytokines they produce. (Activated T4-lymphocytes remain in the lymph node as they proliferate (clonal expansion) and only leave the lymphoid tissues and re-enter the bloodstream after they have differentiated into effector T4-lymphocytes.)

CD28-dependent co-stimulation of the T4-lymphocyte also stimulates it to synthesize the cytokine interleukin-2 (IL-2) as well as a high-affinity IL-2 receptor. The binding of IL-2 to its high affinity receptor allows for cell proliferation and formation of a clone of thousands of identical T4-lymphocytes after several days. IL-2 also contributes to survival of those activated T4-lymphocytes and their differentiation into T4-effector cells. In addition, some of the T4-lymphocytes differentiate into circulating T4-memory cells. Circulating T4-memory cells allow for a more rapid and greater production of effector T4-lymphocytes upon subsequent exposure to the same antigen.

Differentiation of naive T4-lymphocyte into T4-effector lymphocytes

Functionally, there are many different types or subpopulations of effector T4-lymphocytes based on the cytokines they produce. Immune reactions are typically dominated by five primary types: TH1 cells, TH2 cells, TH17 cells, Treg cells, and TFH cells.

CD4 TH1 cells

Coordinate immunity against intracellular bacteria and promote opsonization. They:

  1. Produce cytokines such as interferon-gamma (IFN-?) that promote cell-mediated immunity against intracellular pathogens, especially by activating macrophages that have either ingested pathogens or have become infected with intracellular microbes such as Mycobacterium tuberculosis, Mycobacterium leprae, Leishmania donovani, and Pneumocystis jjroveci that are able to grow in the endocytic vesicles of macrophages. Activation of the macrophage by TH1 cells greatly enhances their antimicrobial effectiveness.
  2. They produce cytokines that promote the production of opsonizing antibodies that enhance phagocytosis (Figure 9).
  3. Produce receptors that bind to and kill chronically infected cells, releasing the bacteria that were growing within the cell so the can be engulfed and killed by macrophages.
  4. Produce the cytokine interleukin-2 (IL-2) that induces T-lymphocyte proliferation.
  5. Produce cytokines such as tumor necrosis factor-alpha (TNF-a) that promote diapedesis of macrophages.
  6. Produces the chemokine CXCL2 to attract macrophages to the infection site.
  7. Produce cytokines that block the production of TH2 cells.

CD4 TH2 cells

Coordinate immunity against helminths and microbes that colonize mucous membranes

  1. Produce the cytokine interleukin-4 (IL-4) that promotes the production of the antibody isotype IgE in response to helminths and allergens. IgE is able to stick eosinophils to helminths for extracellular killing of the helminth (Figure 10); it also promotes many allergic reactions.
  2. Produce cytokines that attract and activate eosinophils and mast cells.
  3. Promote the production of antibodies that neutralize microbes (Figure 11) and toxins (Figure 12) preventing their attachment to host cells.
  4. Produce cytokines that function as B-lymphocyte growth factors such as IL-4, IL-5, IL-9. and IL-13 (Figure 13).
  5. Produce interleukin-22 (IL-22) that promotes the removal of microbes in mucosal tissues.
  6. Produce cytokines that block the production of TH1 cells.

CD4 TH17 cells

Promote a local inflammatory response to stimulate a strong neutrophil response and promote the integrity of the skin and mucous membranes

Produce cytokines like interleukin-17 (IL-17) and interleukin-6 (IL-6) that trigger local epithelial cells and fibroblasts to produce chemokines that recruit neutrophils to remove extracellular pathogens.

CD4 Treg cells

Suppress immune responses

  1. Produce inhibitory cytokines such as Interleukin-10 (IL-10) and TGF-ß that help to limit immune responses and prevent autoimmunity by suppressing T-lymphocyte activity.
  2. Promoting anamnestic response (immunologic memory) to resist repeat infections by the same microbe.
  3. Protecting beneficial normal flora in the intestines from being destroyed by the immune system.
  4. Aiding in sustaining pregnancy so that the immune system doesn't recognize a fetus as foreign and try to destroy it.
  5. Controlling established inflammation in tissues.

TFH cells

Promote humoral immunity by stimulating antibody production and antibody isotype switching by B-lymphocytes

  1. T follicular helper cells (TFH cells) are located in lymphoid follicles.
  2. TFH cells are now thought to be the primary effector T-lymphocytes that stimulate antibody production and isotype switching by B-lymphocytes. They are able to produce cytokines that are characteristic of both TH2 cells and TH1 cells.
  3. TFH cells producing (IFN-?) promote the production of opsonizing antibodies; those producing IL-4 promote the production of IgE.

With the exception of TFH cells which remain in the follicular germinal centers of the lymph nodes and the spleen, effector T4-lymphocytes leave the secondary lymphoid organs and enter the bloodstream where they can be delivered anywhere in the body via the circulatory system and the inflammatory response. In addition, some of the T4-lymphocytes differentiate into circulating T4-memory cells. Circulating T4-memory cells allow for a more rapid and greater adaptive immune response upon subsequent exposure to the same antigen.

For a Summary of Key Surface Molecules and Cellular Interactions of Naive T4-Lymphocytes (Figure 14).

Fig. 14: A Summary of Key Surface Molecules and Cellular Interactions of Naive T4-Lymphocytes

Exercise: Think-Pair-Share Questions

Dendritic cells are antigen-presenting cells because they present antigens to naive T4-lymphocytes and naive T8-lymphocytes in order to activate these naive cells.

Macrophages and B-lymphocytes are antigen-presenting cells but they do not activate naive T4- and T8-lymphocytes. Why must macrophages and B-lymphocytes be antigen-presenting cells?

Regulation of effector T4-lymphocyte activity: A role for commensals and helminths?

It is now recognized that genes associated with the normal flora ( microbiota) of the intestinal tract aid in digestion of many foods (especially plant polysaccharides that would normally be indigestible by humans), may play a role in normal growth and regulating appetite, and also help to regulate immune defenses. There is ever growing evidence that commensal bacteria of the gastrointestinal tract, as well as parasitic gastrointestinal helminths, may have coevolved with the human body over the past 200,000 year in such a way that genes from the human microbiota may play a significant role in regulating the human immune responses by providing a series of checks and balances that prevent the immune system from being too aggressive and causing an autoimmune attack upon the body's own cells, while still remaining aggressive enough to recognize and remove harmful pathogens. As exposure to and colonization with these once common human organisms has drastically changed over time as a result of less exposure to mud, animal and human feces,and helminth ova, coupled with ever increasing antibiotic use, improved sanitation, changes in the human diet, increased rate of cesarean sections, and improved methods of processing and preserving of food, the rate of allergies, allergic asthma, and autoimmune diseases (inflammatory bowel disease, Crone's disease, type-1 diabetes, and multiple sclerosis for example) has dramatically increased in developed countries while remaining relatively low in undeveloped and more agrarian parts of the world.

Numerous experiments in germ-free mice (mice with no intestinal commensals) have shown them to be much more susceptible to allergic asthma and autoimmune diseases such as colitis then normal mice. Feeding commensals or nematode ova to newborn germ-free mice, in turn, reduces the occurrence to these disorders. An imbalance in the relationship between proinflammatory TH17 cells and inflammation-suppressing Treg cells appears to increase the risk of inflammatory autoimmune diseases, while an imbalance between TH1 and TH2 cells seems to contribute to the risk of allergies and asthma. For example, a common commensal colon bacterium Bacteroides fragilis produces a molecule called polysaccharide A that dendritic cells engulf, process and present to naive T4-lymphocytes. This interaction stimulates the differentiation of the naive T4-lymphocytes into anti-inflammatory Treg cells that suppress the activity of proinflammatory TH17 cells. Without colonization with B. fragilis, the proinflammatory TH17 cells are not suppressed and there is an increased risk of inflammatory autoimmune diseases.

Normal intestinal microbiota also appear to regulate the intestinal levels of the invariant natural killer (iNKT) cells discussed under innate immune responses in Unit 4. iNKT cells recognize endogenous and exogenous lipid antigens presented on CD1d molecules by dendritic cells and in response, secrete proinflammatory cytokines. Germ free mice show an accumulation of iNKT cells in the colon and in the lungs and have an increased risk of intestinal bowel disease and allergic asthma. Neonatal germ free mice that were subsequently colonized with normal microbiota were protected from this iNKT cell accumulation and the resulting inflammatory pathology.

Summary

  1. T-lymphocytes refer to lymphocytes that are produced in the bone marrow but require interaction with the thymus for their maturation.
  2. The primary role of T4-lymphocytes is to regulate the body's immune responses through the production of cytokines.
  3. T4-lymphocytes display CD4 molecules and T-cell receptors (TCRs) on their surface.
  4. The TCR on T4-lymphocytes, in cooperation with CD4, typically bind peptides from exogenous antigens bound to MHC-II molecules.
  5. During its development, each T4-lymphocyte becomes genetically programmed to produce a TCR with a unique specificity that is able to bind an epitope/MHC-II complex on an APC such as a dendritic cell, a macrophage, or a B-lymphocyte possessing a corresponding shape.
  6. To become activated, naive T4-lymphocytes migrate through lymph nodes where the TCRs on the T4-lymphocyte are able to sample large numbers of MHC-II/peptide complexes on the antigen-presenting dendritic cells for ones that “fit”, thus enabling activation of that naïve T4-lymphocyte.
  7. After activation, the dendritic cell produces cytokines that contribute to proliferation of the T4-lymphocytes and their differentiation into effector T4-lymphocytes, the cells the body uses to regulate both humoral immunity and cell-mediated immunity through the cytokines they produce.
  8. Some of the T4-lymphocytes differentiate into circulating T4-memory cells that enable a more 9.rapid and greater production of effector T4-lymphocytes upon subsequent exposure to the same antigen.
  9. Functionally, there are many different types or subpopulations of effector T4-lymphocytes based on the cytokines they produce. Immune reactions are typically dominated by five primary types: TH1 cells, TH2 cells, TH17 cells, Treg cells, and TFH cells.
  10. CD4 TH1 cells coordinate immunity against intracellular bacteria and promote opsonization.
  11. CD4 TH2 cells coordinate immunity against helminths and microbes that colonize mucous membranes.
  12. CD4 TH17 cells promote a local inflammatory response to stimulate a strong neutrophil response and promote the integrity of the skin and mucous membranes.
  13. CD4 Treg cells suppress immune responses.
  14. TFH cells promote humoral immunity by stimulating antibody production and antibody isotype switching by B-lymphocytes.
  15. There is ever growing evidence that commensal bacteria of the gastrointestinal tract, as well as parasitic gastrointestinal helminths, may have coevolved with the human body over the past 200,000 year in such a way that genes from the human microbiota may play a significant role in regulating the human immune responses by providing a series of checks and balances that prevent the immune system from being too aggressive and causing an autoimmune attack upon the body's own cells, while still remaining aggressive enough to recognize and remove harmful pathogens.

Contributors

  • Dr. Gary Kaiser (COMMUNITY COLLEGE OF BALTIMORE COUNTY, CATONSVILLE CAMPUS)