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Lymphocyte development and survival Chapter 7

Lymphocyte development and survival Chapter 7. 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

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Lymphocyte development and survival Chapter 7

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

  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

  10. B cell development: Expression of Ig

  11. B cell development: Expression of Ig

  12. RAG B cell development: Expression of Ig

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

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

  15. B cell development: Negative selection

  16. B cell development: Negative selection • 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. Testing for appropriate antigen recognition properties (tolerance to self) Activation by antigen B cell development Expression of antigen receptor

  19. B cell development: activation by antigen

  20. B cell development: activation by antigen • Chemokines attract and retain B cells in the lymph nodes • CXCL13

  21. B cell development: activation by antigen

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

  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

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

  29. T cell development Expression of TCR

  30. 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

  31. T cell development: expression of TCR

  32. T cell development: expression of TCR

  33. T cell development: expression of TCR

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

  35. 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

  36. T cell development: Positive selection

  37. T cell development: Positive selection

  38. T cell development: Negative selection

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

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

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

  42. T cell development: activation by antigen

  43. T cell development: activation by antigen • As with B cells, self-reactive T cells can also be eliminated in the periphery • Activation-induced cell death • Anergy

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

  45. 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

  46. T cell cancers

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