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

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

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

4. Innate immunity Adaptive immunity

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

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

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

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

9. Cell survival or death Allelic exclusion

11. Ig gene rearrangement

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

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

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

15. Microenvironment: thymus

16. Site of cell destruction Epithelial cell network: thymic stroma

17. T cell development  TCR

18.  TCR genes

19.  TCR  TCR or ? 

20.  gene rearrangement induces  gene deletion

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

22. Negative selection: self tolerance Bone marrow-derived

23. 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 Negative selection : Self Ag presentation

24. Natural regulatory T cells (Treg)

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

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

27. CD4T  TCR  TCR T cells CD8T MHC-II MHC-I T cell subpopulations T cell development 1. Antigen specificity 2. Diversity 3. Immunological memory 4. Self tolerance

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

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

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

31. Lymph node distribution in the body Lymph node

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

34. Naïve, activated, effector Humoral immunityCell-mediated immunity (CMI) Activation Effector

35. Naïve T cell activation in peripheral lymphoid organs

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

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

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

39. Signal 3: cytokine

40. T H 17 Recruitment of neutrophils Activation of macrophages Antimicrobial peptides Ubiquitous expression of IL17R on tissue cells: fibroblasts, epithelial cells, keratinocytes, etc. Cytokines: G-CSF, GM-CSF Chemokines: CXCL8, CXCL2 Proinflammatory cytokine Antimicrobial peptidesPhagocytosis Inflammed site Signal 1+2

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

42. Cytokines made in the later stages of infection Differentiation of Th1 or Th2 (polarization) IL12 – Th1IL4 – Th2 Intracellular infectionExtracellular infection

43. Adaptive Treg T H 17 Rapid response to infection Preventing anti-self response Inhibition of proliferation & differentiation T H 17 Limiting immunopathology Peripheral tolerance

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

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

46. Effector T cells Membrane effector molecule

48. CMI: Macrophages activated by Th1 APC activation

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

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

51. CD4 T help in B cell differentiation 51

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

53. Adaptive immunity

54. Ab:Affinity maturation Ag Highly sensitive to small amount of Ag CD4 Th2 in B cell differentiation 54 Variable region Ab: class switching

55. Protective immunity & time Apoptosis of effectors Memory cells:long-lived