Immunol mol med 2

1. Immunol mol med 2 Conleth Feighery 2010

2. This lecture ….. • Importance of lymphocytes in immune system • Identification of T and B cells • How these cells bind antigen - receptors • How cells become activated • The involvement of MHC molecules in T cell function

3. Medical journals • It is never too early to start …. dipping into journals 2 you might consider - • New England Journal of Medicine • Lancet

4. Major cells of the immune system lymphocytes monocyte T cell neutrophil dendritic cell B cell

5. 2 types of lymphocytes T Mature in thymus - regulate, kill B Mature in the bursa - antibody

6. Neutrophils ingest foreign material digest it “phagocytosis” • Neutrophils most numerous white cell in circulation • Short lived - 1 day • Non-specific

7. Monocytes Macrophage in tissue “present” antigen monocyte Phagocytic cells 5 % of circulating cells

8. Macrophage

9. Dendritic cells Major antigen presenting cell in tissues T cell - help - suppress - kill B cell antibody Ingested antigen is presented

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

11. Antigen presenting cells - APC • Dendritic cells • Macrophages • B cells

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

13. B cell identification B cells have a specific receptor for antigen antibody receptor binds antigen directly

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

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

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

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

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

19. B cell receptor constant Variable region Variable region The shape of the variable region binds to shape of different antigens.

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

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

22. 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

23. For T cells to function …. • Need TCR - binds antigen • Need CD3 - signals binding via TCR • Need antigen to be “presented” APC • Antigen has to be bound to “MHC” mols.

24. 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

25. 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

26. 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

27. 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.'

28. 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.…”

29. MHC class I on target cell peptide TARGET CELL APC MHC I molecule

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

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

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

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

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

35. B cells act as APC B T h antibody

36. T cell stimulation • T cells bind to antigen and MHC • Need to bind to a second molecule for full stimulation

37. 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

38. 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

39. 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

40. CD4+ T cells - MHC II interaction CD4 T h APC B7 CD28 cytokines

41. CD4+ T cells interact with APC and other cells by releasing cytokines. APC also release cytokines. CD4 T h APC B7 CD28 cytokines The type of cytokines that are released are crucial to the type of immune response which results

42. 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 !