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Chapter 8

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  1. Chapter 8 B T B/T cell development

  2. Innate immunity Pattern recognition Adaptive immunity B/T cells BCR/TCR: epitope recognition Gene rearrangement of AgR

  3. Gene rearranged receptors Structure BCR/TCR: Ag recognition Extracellular Ag Epitope MHC-restriction Intracellular Ag

  4. Techniques One cell one Ag-specific receptor Clone 細胞差異 Fate T/B: Rearranged AgR T: MHC restriction

  5. Adaptive immunity Four characteristics 1. Antigen specificity 2. Diversity 3. Immunological memory 4. Self tolerance Foreign (non-self) Ag Self Ag (encoded by the host’s genome)

  6. Aim of development Production of AgR • Productive rearranged AgR 2. Functional Ag recognition 3. Self tolerance Self Ag? MHC-restricted?

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

  8. B-cell development T-cell development Positive & negative selection Fate Self antigen Before or after gene rearrangement of AgR ?

  9. Development of B cells Microenvironment Adhesion molecules Chemokines & R Cytokines & R Stromal cells

  10. The dependence on bone marrow stromal cells Early stages Cell-cell interaction B cell commitment SDF-1 Migration Constitutive production

  11. Gene rearrangement

  12. Gene rearrangement Loop

  13. Ig gene rearrangement & B cell stages Proliferation

  14. Antibody structure

  15. Protein-regulated gene rearrangement

  16. Cell survival or death Allelic exclusion One cell one Ag-specific receptor

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

  18. Low frequency of Ag-specific B cells

  19. 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, .. Protein-regulated gene rearrangement One cell one AgR Cell survival & death

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

  21. T cell development

  22. Epithelial cell network: thymic stroma Thymus

  23. gdTCR

  24. ab TCR genes

  25. abTCR or gdTCR ? b

  26. Developmental control of gd T cells Ordered sequence

  27. Repeated rearrangements can rescue nonproductive VaJa joins

  28. a gene rearrangement induces d gene deletion

  29. T cell commitment R: Notch 1

  30. T cell development Gene rearrangement Cortex Medulla Positive selection : MHC restriction Negative selection : Self tolerance

  31. Self MHC restriction

  32. T cell development MHC Positive selection : MHC restriction Negative selection : Self tolerance

  33. MHC Gene locus

  34. H-2k

  35. 親代來源 H-2k 基因

  36. Analyze all the possible types of MHC class I and II restriction for CD4 T and CD8 T cells developed in an MHCbxk F1 hybrid mouse.

  37. Ch6 section 6-12 MHC: co-dominant d/k

  38. ?

  39. TCR: MHC restriction MHC polymorphism 個體獨特性 MHC haplotype Ch6 section 6-12

  40. MHC polymorphism Alleles / locus Formula: 100(DPa) X 100(DPb) X 100(DQa) X 100(DQb) X 100(DRa) X 100(DRb) X 100(A) X 100(B) X 100(C) =1018

  41. Variability of MHC alleles

  42. MHC I Peptide presented on MHC I/II MHC II

  43. MHC-binding ability of peptides Multiple epitopes

  44. MHC-restricted presentation of antigenic peptides d/k

  45. Positive selection : MHC restriction H-2k Self MHC restriction 3 2

  46. d/k Self MHC restriction 3 6 2 8

  47. MHC and immune responsiveness