1. The development of lymphocytes
Ch8
The development of lymphocytes

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

3. Ags………. Gene rearranged receptors: TCR/BCR Germline-encoded receptors
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 Self Ag? MHC-restricted? 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. One receptor on one cell
Heavy chain
One receptor
on one cell
Allelic exclusion

15. Protein-regulated gene rearrangement

18. Protein-regulated gene rearrangement

19. Cell survival or death

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

21. Receptor editing 21

22. 7-8
Fig. 7-23 22

23. T B-cell development Stromal cell-dependent (Spatial regulation)
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, ..)

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

25. Affinity

26. Epithelial cell
network:
thymic stroma
Thymus 26

27. 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

28. Cells & microenvironment

29. Flow cytometry

30. T cell
development
gdTCR

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

32. T cell commitment
R: Notch 1

33. Microenvironment

34. abTCR or
gdTCR ? b

35. Developmental
control of
gd T cells
Ordered sequence

36. abTCR or
gdTCR ? b

37. Cells
Repeated rearrangements can rescue nonproductive VaJa joins 37

38. a gene rearrangement induces d gene deletion

39. 39

40. Microenvironment After TCR rearrangement MHC restriction
Self tolerance 40

41. Positive selection :
MHC restriction
Cortex
MHCI-CD8
MHCII-CD4 41

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

43. Ag encounter in periphery
Bone marrow-derived
DC/macrophages 43

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

45. Negative selection: self tolerance
Bone marrow-derived 45

46. Negative selection : Self tolerance
AIRE expression on thymic medulary cells
Medulary epithelial marker MTS10
Self antigen
(encoded by the host’s genome)
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

47. Microenvironment
MHC restriction
Self tolerance
affinity 47

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

49. 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

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

51. Techniques
Adoptive transfer 51

52. Techniques
Hormone
Transgenic mice
Fertilized egg
Transgene

53. Hybridoma
TCR transgene

54. Knock-out
mice

55. Knock-out
mice

56. 黑 白
Knock-out
mice
Knock-in
mice
Lethal effect

57. Positive selection MHC II restriction: Interaction of CD4 with MHCII
Host 57

58. Inducible knock-out mice
Tissue specificity
Cre/lox system
Enzyme
(recombinase)
in other tissues