1. Immunology molecular medicine 3 Conleth Feighery

2. Learning objectives T cell binding to APC essential for T cell stimulation T cell cytokines – determine their effect APC use pattern recognition receptors The structure of the T cell receptor

3. CYTOKINES Cells of the immune system ‘talk’ to each other by producing cytokines - like ‘text messages’ informing cells what their function should be!

4. CD4+ T cells - MHC II interaction APC T h cytokines

5. CD4+ T cells interact with APC and other cells by releasing cytokines. APC also release cytokines. APC T h cytokines The type of cytokines that are released are crucial to the type of immune response which results

6. Cytokine products of cells APC T h IL-1 IL-2 CD28 B7

7. Cytokine product of cells APC T h IL-1 IL-2 Cells interact through the production and release of cytokines - these bind to cells and affect their function CD28 B7

8. Cytokine products of cells APC T h IL-1 IL-2 Receptors - cytokines bind to specific cell receptors

9. Cytokines Small protein molecules c. 20,000 aa Specific types produced by different cells Bind to cells and affect cell function Some are called “interleukins” or IL

10. IL-1 helps T cell activation APC T h IL-1 produced by APC

11. T cell co-stimulation Essential to T cell activation, division and replication

12. Activation of T cells Requires 2 signals Signal 1 - TCR, MHC, antigen Signal 2 - CD28 binding to B7 Both signals must be from the same APC ONLY now can T cell proliferation start

13. CD4+ T cells - activation requires 2 signals APC T h CD4 T cell receptor binding to antigen = signal 1 CD28 B7 CD28 binds to B7 = signal 2

14. Stimulated T cell - IL-2 produced APC T h CD4 CD28 B7 IL-2 IL-2 receptor IL-2 binds to receptor on cell - causes cell growth, division

15. IL-2 required for T cell growth APC T h IL-2 CD28 B7

16. CTLA-4 - negative signal APC T h CD4 T cell receptor binding to antigen = signal 1 CTLA-4 B7 CTLA-4 binds to B7 - inhibits stimulation

17. T cell cytokines affect B cells T h B IL-4,5,6

18. T cell cytokines affect B cells T h B IL-4, IL-5, IL-6 IL-4, 5 and 6 all involved in B cell stimulation and Ig production

19. Lymph node - cartoon Alberts et al. T cell activation takes place in lymph node tissue T cell help for B cells takes place in lymph. follicles

20. Lymph node - histology Lymphoid follicles

21. Interferon gamma helps kill intracellular infections MO T h TB Interferon - gamma IFN-  IFN-  activates macrophage killing mechanisms

22. T cytotoxic cell - recognition of antigen, role of CD8 APC T cytx T cytotoxic cell reacting with virus antigen presented by MHC class I molecule CD8 MHC I Target cell virus

23. CD8+ T cells can kill target cells by inserting a ‘perforating hole’ in the cell, through which enzymes enter, damaging the cell APC T cytx TARGET CELL CD8 perforin enzymes

24. T cytotoxic cell - cytolytic mechanism APC T cytx Target cell virus Lytic granules perforin Enzymes, water, salts Granules - content perforin, enzymes

25. Pattern recognition receptors Various stimuli bind to receptors on APC and influence APC reaction APC TOLL Stimulus

26. Pattern recognition receptors Various stimuli bind to receptors on APC and influence APC reaction Different cytokines APC B7 Toll-like receptors Stimulus

27. APC –effect on T cell response APC Stimulus TH 1 TH 2 T reg IFN-  IL-4 IL-10

28. APC - effect on T cell response TH 1 TH 2 T reg IFN-  IL-4 IL-10 APC Stimulus

29. Cytokines and T cells Depending on the antigen, APC may produce different sets of cytokines These cytokines determine the type of T cell that proliferates Different types of T cells produce specific sets of cytokines

30. Structure of molecules of IS T cell receptor or TCR MHC class I MHC class II Antibody molecules Knowledge of these structures is helpful in understanding how immune system functions

31. TCR - alpha, beta chains alpha chain beta chain variable region constant region

32. T cell receptor structure Alberts et al.

33. TCR - gamma, delta chains gamma chain delta chain variable region constant region

34. Immunoglobulin super-family Many molecules in the immune system have an Ig-like structure and hence, belong to the “Ig superfamily”. Alberts et al.

35. MHC I and II structure Alberts et al.