Differentiation and Functions of CD4+ Effector T Cells

1. Differentiation and Functions ofCD4+ Effector T Cells Chapter 10

3. Cell-mediated immunity (CMI) is the type of host defense that is mediated by T lymphocytes, and it serves as a defense mechanism against intracellular and phagocytosed microbes

4. Reactions of CD4+ T cells in cell-mediated immunity

5. Cell-mediated immunity to Listeriamonocytogenes • In CMI responses against phagocytosed microbes, T cells specifically recognize microbial antigens but phagocytes actually destroy the pathogens • Inflammation, consisting of leukocyte recruitment and activation, accompanies many of the reactions of CD4+ T lymphocytes and may damage normal tissues. This T cell–dependent injurious reaction is called delayed-type hypersensitivity (DTH)

6. SUBSETS OF CD4+ EFFECTOR T CELLS

7. The Th1 Subset • The TH1 subset is induced by microbes that are ingested by and activate phagocytes, and is the major effector T cell population in phagocyte-mediated host defense, the central reaction of cell-mediated immunity • TH1 differentiation is driven mainly by the cytokines IL-12 and IFN-γ and occurs in response to microbes that activate dendritic cells, macrophages, and NK cells

8. Development of TH1 cells

9. Functions of TH1 cells

10. Interferon-γ • IFN-γ is the principal macrophage-activating cytokine and serves critical functions in immunity against intracellular microbes • IFN-γ activates macrophages to kill phagocytosed microbes • IFN-γ acts on B cells to promote switching to certain IgG subclasses, notably IgG2a or IgG2c (in mice), and to inhibit switching to IL-4–dependent isotypes, such as IgE • IFN-γ promotes the differentiation of CD4+ T cells to the TH1 subset and inhibits the development of TH2 and TH17 cells • IFN-γ stimulates expression of several different proteins that contribute to enhanced MHC-associated antigen presentation and the initiation and amplification of T cell–dependent immune responses

11. Other TH1 Cytokines • In addition to IFN-γ, TH1 cells produce TNF and various chemokines, which contribute to the recruitment of leukocytes and enhanced inflammation. Somewhat surprisingly, TH1 cells are also important sources of IL-10, which functions mainly to inhibit dendritic cells and macrophages and thus to suppress TH1 activation. This is an example of a negative feedback loop in T cell responses.

12. Macrophage activation by TH1 cells

13. Classical and alternative macrophage activation

14. THE TH2 SUBSET

15. Functions of TH2 cells

16. Cytokines Produced by TH2 Cells • Interleukin-4 (IL-4) • IL-4 is the major stimulus for the production of IgE antibodies and for the development of TH2 cells from naïve CD4+ helper T cells • IL-4 stimulates B cell Ig heavy chain class switching to the IgE isotype • IL-4 stimulates the development of TH2 cells and functions as an autocrine growth factor for differentiated TH2 cells • IL-4, together with IL-13, contributes to an alternative of macrophage activation • IL-4 (and IL-13) stimulate peristalsis in the gastrointestinal tract, and IL-13 increasesmucus secretion from airway and gut epithelial cells • IL-4 and IL-13 stimulate the recruitment of leukocytes

17. Interleukin-13 • IL-13 is structurally and functionally similar to IL-4 and also plays a key role in defense against helminths and in allergic diseases • IL-13 is produced mainly by the TH2 subset, but basophils, eosinophils, and NKT cells • The receptor is expressed on a wide variety of cells, including B cells, mononuclear phagocytes, dendritic cells, eosinophils, basophils, fibroblasts, endothelial cells, and bronchial epithelial cells. T cells do not express the IL-13 receptor • IL-13 works together with IL-4 in producing biologic effects associated with allergic inflammation

18. Interleukin-5 • IL-5 is an activator of eosinophils and serves as the principal link between T cell activation and eosinophilic inflammation • The principal actions of IL-5 are to activate mature eosinophils and to stimulate the growth and differentiation of eosinophils

19. THE TH17 SUBSET • TH17 cells secrete cytokines that recruit leukocytes, mainly neutrophils, to sites of infection • Most of the inflammatory actions of these cells are mediated by IL-17, but other cytokines produced by this subset may also contribute

20. Development of TH17 cells

21. Functions of TH17 cells

22. Interleukin-17 • IL-17 is an unusual cytokine because neither it nor its receptor is homologous to any other known cytokine receptor pair • The IL-17 family includes six structurally related proteins, of which IL-17A and IL-17F are the most similar, and the immunologic activities seem to be mediated primarily by IL-17A. IL-17A and IL-17F are produced mainly by TH17 cells • IL-17 is an important link between T cell–mediated adaptive immunity and the innate immune system, especially the inflammatory component of innate responses • IL-17 induces neutrophil-rich inflammatory reaction • IL-17 stimulates the production of antimicrobial substances, including defensins, from numerous cell types

23. Other TH17 Cytokines • IL-22 is a member of the IL-10 cytokine family. It is produced by activated T cells, particularly TH17 cells, and by NK cells. The actions of IL-22 appear contradictory. Some studies indicate that it contributes to inflammation and tissue injury, but the bulk of the available data suggests that it is produced in epithelial tissues, especially of the skin and gastrointestinal tract, and serves to maintain epithelial integrity, mainly by promoting the barrier function of epithelia and by stimulating repair reactions • IL-21 is produced by activated CD4+ T cells, including TH17 cells, which has a wide variety of effects on B and T cells and NK cells. An important function of IL-21 is in antibody responses, especially the reactions that occur in germinal centers. IL-21 is required for the generation of follicular helper T cells and is also produced by follicular helper cells and stimulates B cells in germinal centers

24. FUNCTIONS OF OTHER T CELL SUBSETS • γδ T Cells • Less than 5% of all T cells express this form of TCR • The limited diversity of the γδ TCRs in many tissues suggests that the ligands for these receptors may be invariant and conserved • More than 50% of lymphocytes in the small bowel mucosa of mice and chickens, called intraepithelial lymphocytes, are γδ T cells. In mouse skin, most of the intraepidermal T cells express the γδ receptor • Only about 10% of human intestinal intraepithelial T cells express the γδ TCR • γδ T cells do not recognize MHC-associated peptide antigens and are not MHC restricted

25. Some γδ T cell clones recognize small phosphorylated molecules, alkylamines, or lipids that are commonly found in mycobacteria and other microbes and that may be presented by “non-classical” class I MHC–like molecules • Many γδ T cells are triggered by microbial heat shock proteins • A number of biologic activities have been ascribed to γδ T cells, including secretion of cytokines and killing of infected cells, but the function of these cells remains poorly understood

26. NKT Cells • A small population of T cells also expresses markers that are found on NK cells, such as CD56; these are called NKT cells • Because of this limited diversity, these cells are also called invariant NKT (iNKT) cells • All NKT cell TCRs recognize lipids that are bound to class I MHC–like molecules called CD1 molecules • NKT cells are capable of rapidly producing cytokines such as IL-4 and IFN-γ after activation, and they may help marginal zone B cells to produce antibodies against lipid antigens