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Germline-encoded receptors

Innate immunity. Ags………. Germline-encoded receptors. Pattern recognition. Adaptive immunity. Gene rearranged receptors: TCR/BCR. B/T cells. Epitope recognition. ?. Ags………. Foreign Ag Self Ag. 自我耐受性. Self tolerance. Ag recognition. Gene rearranged receptors. Structure.

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Germline-encoded receptors

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  1. Innate immunity Ags………. Germline-encoded receptors Pattern recognition Adaptive immunity Gene rearranged receptors: TCR/BCR B/T cells Epitope recognition

  2. ? Ags………. Foreign Ag Self Ag 自我耐受性 Self tolerance Ag recognition

  3. Gene rearranged receptors Structure BCR/TCR: Ag recognition Variable region Extracellular Ag Light chain (L) Heavy chain (H) MHC-restriction Fig. 5.1 Intracellular Ag

  4. Innate immunity Adaptive immunity

  5. Hematopoiesis 2 Central lymphoid organs Microenvironment Commitment Productive rearrangement? Cell survival & death

  6. Adaptive immunity Immune diversity Clonal selection Bone marrow 骨髓 Thymus 胸腺 Gene rearrangement of TCR/BCR Antigen specificity Diversity Memory Note: low frequency of Ag-specific cells Peripheral tolerance Clone Central tolerance

  7. Adaptive immunity Four characteristics 1. Antigen specificity 2. Diversity 3. Immunological memory 4. Self tolerance

  8. One receptor on one cell Heavy chain Co-dominant Allelic exclusion

  9. Cell survival or death Allelic exclusion

  10. Ig gene rearrangement

  11. BM microenvironment Adhesion molecules Chemokines & R Cytokines & R Stromal cells

  12. The dependence on bone marrow stromal cells Early stages Cell-cell interaction SDF-1 Migration

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

  14. Microenvironment: thymus

  15. Epithelial cell network: thymicstroma Site of cell destruction

  16. T cell development gdTCR

  17. ab TCR genes

  18. abTCR or gdTCR ? b

  19. a gene rearrangement induces d gene deletion

  20. Positive selection : MHC restriction MHCI-CD8 MHCII-CD4

  21. Negative selection: self tolerance Bone marrow-derived

  22. Negative selection : Self Ag presentation AIRE expression on thymic medulary cells (Autoimmune regulator) Medulary epithelial marker MTS10 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

  23. Natural regulatory T cells (Treg)

  24. Negative selection : clonal deletion & Treg Ann Rev Immunol 30: 531, 2012

  25. T cell development AIRE medulary cells Natural Treg The presence of autoreactive lymphocytes in periphery

  26. T cell development T cell subpopulations T cells gd TCR ab TCR 1. Antigen specificity 2. Diversity 3. Immunological memory 4. Self tolerance CD4T CD8T MHC-I MHC-II

  27. Adaptive immunity Induction of adaptive immunity Differentiation of Th Cytokines Cell-mediated immunity Humoral immunity Immunological memory

  28. Immunity & Ag location Humoral response Ag Innate Adaptive Extracellular Phagocytes B cells Intracellular NK CD8 Tc cells (Altered self) Th2 CD4 Th Th1 Cytotoxicity Cell-mediated immunity (CMI)

  29. Induction of adaptive immunity Phagocytes Inflammation Dendritic cells (DC) Antigen-Presenting Cells (APC) Lymph node B/T cells Lymphocyte activation Clonal selection Humoral Imm/CMI Memory Inflammatory site Inflammatory site

  30. Lymph node Lymph node distribution in the body

  31. Immune effector function Induction of adaptive immunity Differentiation of CD4 Th Cytokines Cell-mediated immunity Humoral immunity Immunological memory

  32. Naïve, activated, effector Activation Effector Cell-mediated immunity (CMI) Humoral immunity

  33. Naïve T cell activation in peripheral lymphoid organs

  34. Priming The activation and differentiation of naïve T cells Three signals in naïve T cell activation Costimulation

  35. Signal 1+2 CD4 T cell activation IL2R IL2 production Clonal expansion

  36. CD4 T cell differentiation Th17 Treg Promote local inflammation CMI: CD8 T Humoral response

  37. Signal 3: cytokine

  38. TH17 Proinflammatory cytokine Signal 1+2 Ubiquitous expression of IL17R on tissue cells: fibroblasts, epithelial cells, keratinocytes, etc. Antimicrobial peptides Cytokines: G-CSF, GM-CSF Chemokines: CXCL8, CXCL2 Recruitment of neutrophils Inflammed site Antimicrobial peptides Phagocytosis Activation of macrophages

  39. 10 BM: 10 /day During acute inflammation: 10 fold increase of production

  40. Cytokines made in the later stages of infection Differentiation of Th1 or Th2 (polarization) Intracellular infection Extracellular infection IL12 – Th1 IL4 – Th2

  41. Limiting immunopathology Rapid response to infection Preventing anti-self response Peripheral tolerance TH17 Adaptive Treg Inhibition of proliferation & differentiation TH17

  42. Regulation among CD4 T subsets Inhibition of early Th17 response Cytokine pattern of the dominant response

  43. Immune effector function Induction of adaptive immunity Differentiation of Th Cytokines Cell-mediated immunity Humoral immunity Immunological memory Effector response

  44. Effector T cells Membrane effector molecule

  45. CMI: Macrophages activated by Th1 APC activation

  46. Immune effector function Induction of adaptive immunity Differentiation of Th Cytokines Cell-mediated immunity Humoral immunity Immunological memory Effector response

  47. B cells as APC Effector Th2 cells Humoral immunity: B cell response

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