1. Lymphocyte development and survival Chapter 7

2. Objectives Describe or construct flow charts showing the stages in development of B cells and T cells, including: –The general characteristics (surface markers, etc) of lymphocytes at each stage –Other types of cells or cytokines that are required at each stage –What happens to cells which fail to complete a stage of development Predict how specific genetic defects would alter lymphocyte development

3. Hematopoiesis Lymphopoiesis mainly occurs in central lymphoid tissues

4. Major stages of development in lymphocytes Expression of antigen receptor Activation by antigen Differentiation Testing for appropriate antigen recognition properties (tolerance to self)

5. Overview of B cell development

6. Overview of T cell development

7. B cell development Expression of antigen receptor (immunoglobulin)

8. B cell development: Expression of Ig Stromal cells in the bone marrow provide cytokines and support required for early B cell development –Interleukin-7 (IL-7) –Cell adhesion molecules (CAMs)

9. B cell development: Expression of Ig

12. RAG

13. B cell development: Expression of Ig Rescue of B cells with nonproductive rearrangments

14. B cell development Expression of antigen receptor Testing for appropriate antigen recognition properties (tolerance to self) Negative selection: selection of cells that do NOT bind to self antigens

15. B cell development: Negative selection

16. Self-reactive B cells may undergo further light chain rearrangement

17. B cell development: Negative selection Some self antigens are only expressed in the periphery High levels of cross-linking antigen in periphery can induce B cell anergy

18. B cell development Expression of antigen receptor Activation by antigen Testing for appropriate antigen recognition properties (tolerance to self)

19. B cell development: activation by antigen

20. Chemokines attract and retain B cells in the lymph nodes –CXCL13

21. B cell development: activation by antigen

22. B cell development Expression of antigen receptor Activation by antigen Differentiation Testing for appropriate antigen recognition properties (tolerance to self)

23. B cell development: differentiation Activated B cells undergo clonal expansion Progeny differentiate into plasma cells or memory B cells –Isotype switching and somatic hypermutation occur

24. B cell cancers B cell tumors arise from cells at various stages of development Retain characteristics of the normal B cell equivalent

25. Overview of T cell development

26. Some lymphoid progenitors migrate to the thymus

27. The importance of the thymus for T cell development

29. T cell development Expression of antigen receptor Activation by antigen Differentiation Testing for appropriate antigen recognition properties (tolerance to self)

30. T cell development Expression of TCR

31. T cell development: expression of TCR Progenitors arriving from the bone marrow do not express TCR, CD3, CD4, or CD8 Successful rearrangement of TCR  chain results in expression of a pre-T-cell receptor, CD3, CD4, and CD8

32. T cell development: expression of TCR

35. T cell development Expression of TCR Testing for appropriate antigen recognition properties (tolerance to self)

36. T cell development: selection for self-tolerance Selection for self-tolerance in T cells requires two stages: –Positive selection for ability to bind to MHC : peptide complexes –Negative selection eliminates T cells with high-affinity binding to MHC : self peptide complexes

37. T cell development: Positive selection

39. T cell development: Negative selection

40. The role of thymic cells in positive and negative selection

41. Mechanisms of positive and negative selection Mechanisms that differentiate positive and negative selection are not clear –Difference in affinity? –Other signals required?

42. T cell development Expression of TCR Activation by antigen Testing for appropriate antigen recognition properties (tolerance to self)

43. T cell development: activation by antigen

44. As with B cells, self-reactive T cells can also be eliminated in the periphery –Activation-induced cell death –Anergy

45. T cell development Expression of TCR Activation by antigen Differentiation Testing for appropriate antigen recognition properties (tolerance to self)

46. T cell development: differentiation Activated T cells undergo clonal expansion Differentiation of progeny into effector or memory cells –Cytotoxic T lymphocytes –Helper T cells (Th1, Th2) –Memory T cells

47. T cell cancers