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The development of lymphocytes

Ch8. The development of lymphocytes. Immune system. Design for living. Boundary. Self/non-self recognition. Ags………. Innate immunity. Germline-encoded receptors. Adaptive immunity. Gene rearranged receptors: TCR/BCR. Lymphopoiesis. B/T cell development. Cells

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The development of lymphocytes

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  1. Ch8 The development of lymphocytes

  2. Immune system Design for living Boundary Self/non-self recognition

  3. Ags………. Innate immunity Germline-encoded receptors Adaptive immunity Gene rearranged receptors: TCR/BCR Lymphopoiesis

  4. B/T cell development Cells Microenvironment AgR

  5. Adaptive immunity 1. Antigen specificity 2. Diversity 3. Immunological memory 4. Self tolerance

  6. Aim of development • Production of AgR 2. Functional Ag recognition Self Ag? MHC-restricted?

  7. Hematopoiesis Central lymphoid organs Microenvironment Commitment Productive rearrangement? Cell survival & death

  8. One cell one AgR Clone Fate

  9. B-cell development T-cell development Positive & negative selection

  10. B cell development Die Microenvironment Survive

  11. Transcription factors Proteins, receptors

  12. The dependence on bone marrow stromal cells Adhesion molecules Early stages Growth factors Cell-cell interaction B cell commitment Proliferation (SDF-1) Constitutive production

  13. Ig gene rearrangement

  14. Heavy chain One receptor on one cell Allelic exclusion

  15. Protein-regulated gene rearrangement

  16. Protein-regulated gene rearrangement

  17. Cell survival or death

  18. Self-reactivity Fate The presence of autoreactive lymphocytes in periphery

  19. Receptor editing

  20. 7-8 Fig. 7-23

  21. T B-cell development B cell commitment BCR rearrangement Cell survival & death (BCR, self tolerance) Stromal cell-dependent (Spatial regulation) Temporal regulation of protein expression Proteins: receptors, cytokines, TS factors, recombinase, ..)

  22. T cell development Self MHC restriction Self tolerance Cells Microenvironment

  23. Affinity

  24. Epithelial cell network: thymic stroma Thymus

  25. The importance of thymus in T-cell development Thymectomy DiGeorge’s syndrome Defective repairing system Genetic defect of a gene coding for transcription factor Wnt required for terminal differentiation of cortical epithelial cells

  26. Cells & microenvironment

  27. Flow cytometry

  28. T cell development gdTCR

  29. T cell subsets in central and peripheral organs Flow cytometry: immunostaining Normal

  30. T cell commitment R: Notch 1

  31. Microenvironment

  32. abTCR or gdTCR ? b

  33. Developmental control of gd T cells Ordered sequence

  34. abTCR or gdTCR ? b

  35. Cells Repeated rearrangements can rescue nonproductive VaJa joins

  36. a gene rearrangement induces d gene deletion

  37. After TCR rearrangement Microenvironment MHC restriction Self tolerance

  38. Positive selection : MHC restriction Cortex MHCI-CD8 MHCII-CD4

  39. Positive selection (T cell precursor) T cells : thymus MHC restriction

  40. Ag encounter in periphery Bone marrow-derived DC/macrophages

  41. Bone marrow chimera Thymic non-lymphoid stroma Bone marrow-derived APC

  42. Negative selection: self tolerance Bone marrow-derived

  43. Self antigen (encoded by the host’s genome) Negative selection : Self tolerance AIRE expression on thymic medulary cells Medulary epithelial marker MTS10 AIRE (Autoimmune regulator) AIRE regulates the expression of ubiquitous self antigens & a wide variety of tissue-restricted self Ag (e.g. pancreas, brain) at low levels in the thymus

  44. Microenvironment MHC restriction Self tolerance affinity

  45. T cell development AIRE medulary cells Central tolerance The presence of autoreactive lymphocytes in periphery

  46. The development of lymphocytes 重要性 細胞 地點 時間 如何運作 結果 特性 比較異同

  47. Adaptive immunity 1. Antigen specificity 2. Diversity 3. Immunological memory 4. Self tolerance

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