Immunology 2 nd Med 2009

1. Immunology 2nd Med 2009 Some revision points Con Feighery

2. Lecture content • How to recognise T cells and B cells • Structure of the T cell receptor • The different types of T cells • The role of MHC in activation of T cells • How cytokines influence the immune system

3. Monocytes / macrophages T cell - help - suppress - kill B cell antibody Ingested antigen is presented

4. Antigen presenting cells - APC • Macrophages • Dendritic cells • B cells Dendritic cell

5. B cell identification B cells have a specific receptor for antigen antibody molecule

6. B cell identification B cells have a specific receptor for antigen antigen can bind directly to this receptor

7. T cell identification T cells have a specific receptor for antigen TCR = T cell receptor

8. CD3 on T cells CD3 molecule bound to TCR CD3 signals to cell interior

9. T cell receptor - 2 chains alpha chain beta chain

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

11. TCR - alpha, beta chains constant region variable region The shape of the variable region binds to the shape of different antigens. variable region

12. T helper cells -CD4+ T cells CD4 molecules on T helper cells

13. T cytotoxic cells -CD8+ T cells CD8 molecules on T cytotoxic cells

14. T cell molecules • T cell receptor = TCR • CD3 - signaling molecule • CD4 - on T helper cells • CD8 - on T cytotoxic cells • “CD” = cluster of differentiation - used in describing many molecules of immune system

15. For T cells to function …. • Need TCR - binds antigen • Need CD3 - signals binding • Need antigen to be “presented” APC • Antigen has to be bound to “MHC” mols. • Co-stimulation signal to T cell ….

16. MHC molecules Major Histocompatability Complex = MHC • 2 types • MHC class I • MHC class II • Enable T cells to react with antigen • MHC = transplantation antigens - also called HLA molecules = human leucocyte antigens

17. CD8+ T cells - MHC I interaction CD8 TARGET CELL T cytx APC CD8+ T cells interact with antigen bound to MHC class I The CD8 molecule binds exclusively to MHC class I

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

19. MHC class I • Found on all cells in the body • Essential for function of T cytotoxic cells • Viral peptides bind to MHC I Top end of a MHC class I molecule

20. Don Wiley, died 2001 Scientist, crystallographer I'm sorry, but I just don't understand anything in biology unless I know what it looks like.'

21. Don Wiley - appreciation "Wiley was a crystallographer: this is the ultimate molecular biology. ...The image of a class I MHC protein with its peptide cargo firmly in place will stand as a landmark Wiley discovery that forever changed the field of immunology.…”

22. CD4+ T cells - MHC II interaction CD4 T h APC MHC II with peptide

23. CD4+ T cells - MHC II interaction CD4 T h APC CD4+ T cells interact with antigen bound to MHC class II molecules

24. MHC class II Found on few cells in body - • Macrophages • Dendritic cells • B cells All these cells present antigen = antigen presenting cells or APC

25. MHC class II on APC APC MHC II with peptide

26. MHC class II on B cells B MHC II with peptide antibody

27. B cells act as APC B T h antibody

28. Structure of molecules of IS • T cell receptor • MHC class I • MHC class II • Antibody molecules Knowledge of these structures helps understand how the immune system works !

29. Structure of molecules of IS • T cell receptor • MHC class I • MHC class II • Antibody molecules Knowledge of these structures helps understand how the immune system works !

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

31. T cell receptor structure Alberts et al.

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

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

34. MHC I and II structure Alberts et al.

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

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

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

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

39. 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

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

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

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

43. 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

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

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

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

47. Bi-directional flow of cytokines T h APC cytokines

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

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

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