Chapter 10 T-Cell Maturation, Activation, and

1. Chapter 10 T-Cell Maturation, Activation, and Differentiation

2. 本章大綱: • T-Cell Maturation and the Thymus • Thymic Selection of the T-Cell Repertoire • TH-Cell Activation • T-Cell Differentiation • Cell Death and T-Cell populations • Peripheral gd T-Cells

3. T-Cell Maturation and the Thymus

4. The Human Lymphoid System

5. The Normal Rat Thymus

6. The Thymus stromal cells: maturation

7. Two-step Selection Process of Thymocytes Positive Selection: permits the survival of only those T cells whose TCRs recognize self-MHC molecules. Negative Selection: eliminates T cells that react too strongly with self-MHC or with self-MHC plus self-peptides. Thymic stromal cells, which express high levels of class I and class II MHC molecules, play a role in this process.

8. - Any developing thymocytes that are unable to recognize • self-MHC molecules or that do have a high affinity for • self-Ag plus self-MHC (or self-MHC alone) are eliminated • by programmed cell death. • Thus, only those cells whose receptors recognize a self- • MHC molecules plus foreign Ag are allowed to mature. • - An estimated 95%--99% of all thymocyte progeny undergo • programmed cell death within the thymus without ever • maturing.

9. Various features used to characterize the • pathway of T-cell development in the thymus • TCR-gene rearrangement • Activity of genes, such as RAG-1 and RAG-2, that are • involved in TCR rearrangement • 3. Display of surface Ags specific for T-cell differentiation. • TCR • CD4 • CD8

10. Proposed Pathways for Murine T-cell Development in the thymus • Most of the immune thymocytes in the thymus die • either because they make an unproductive TCR-gene • rearrangement or because they fail positive or • negative selection. • Mature T-cell populations are produced and move to • the peripheral lymphoid organs. • Most T cells express the ab TCR and either CD4 or • CD8. A few T cells express the gd TCR; most of these • lack both CD4 and CD8.

11. receptor for stem-cell growth factor adhesion molecule IL-2Ra

12. Time Course of Appearance of gd Thymocytes and ab Thymocytes During Mouse Fetal Development

13. General Structure of the Pre-TCR and Effects of Activating it

14. Effects of Signal Transduction • through the pre-TCR • - A productive TCR b-chain rearrangement has been • made and selects those thymocytes expressing the b • chain for further expansion and maturation • Suppresses further rearrangement of TCR b-chain • genes, resulting in allelic exclusion of the b chain • -Enhances rearrangement of the TCR a chain • Induces developmental progression to the CD4+CD8+ • double-positive state

15. Thymic Selection of the T-Cell Repertoire

16. The Thymus Selects for Maturation Only Those T Cells Whose TCRs Recognize Ag Presented on Target Cells with the Haplotype of the Thymus

18. Positive and Negative Selection of Thymocytes in the Thymus

19. Acquisition of MHC Restriction Depends on Interaction of Immature Thymocytes with Class I or Class II MHC Molecules on Epithelial Cells

21. CD8+ T Cells Only Mature in Transgenics with the Haplotype (H-2k) Corresponding to the MHC Restriction of the TCR Transgene

22. Negative Selection of Thymocytes Requires Self-Ag Plus Self-MHC

23. TH -Cell Activation

25. Some Common Themes in Signal Transduction • The involvement of a receptor. • The generation of second messengers. • The action of protein kinases and protein phosphatases. • The induced assembly of critical components of a signal • transduction pathway. • Cascades. • The involvement of large and small G proteins. • The default setting for signal transduction pathways is • OFF.

26. Initial Steps in TH-Cell Activation ITAM: immunoreceptor tyrosine-based activation motif

28. Overview of Signal Transduction During T-Cell Activation

29. Mechanism of Immunosuppression by Cyclosporin A (CsA) and FK506

30. TH- Cell Activation Requires a Co-stimulatory Signal Provided by APC

31. Naïve T Cells Require 2 Distinct Signals for • Activation and Proliferation into Effector Cells • The initial signal (signal 1) is generated by interaction • of an antigenic peptide with the TCR-CD3 complex. • A subsequent Ag-nonspecific co-stimulatory signal • (signal 2) is provided primarily by interactions between • CD28 on the T cell and members of the B7 family on • the APC.

32. Clonal Expansion versus Clonal Anergy CD28 no signal 2

33. no signal 2

34. The Resulting Anergic T Cells Cannot Respond to Normal APCs

35. signal 1 signal 2

36. signal 1 signal 2

37. Superantigen-mediated Crosslinkage of T-cell Receptor and Class II MHC Molecules various bacterial Mls Ags encoded by mouse exotoxins mammary tumor virus

41. T-Cell Differentiation

42. Up-regulation of IL-2 and High-affinity IL-2R after the Activation of a TH Cell

43. TH Cells: TH1 subset: secretes IL-2, IFN-g, and TNF-b cell-mediated functions TH2 subset: secretes IL-4, IL-5, IL-6, and IL-10 helper for B-cell activation

44. T Cell Activation Induced by Different APCs

45. Cell Death and T-Cell Populations

46. T Cell Death Trigged by Many Different Induction Pathways

47. Fas-induced Cell Death AICD: activation induced cell death

48. Peripheral gd T Cells

49. gd T cells • In humans, gd T cells < 5% • In mice, gd T cells in lymphoid organs ~ 1% to 3%, • abundant in the skin and intestinal epithelium • intraepidermal lymphocytes: • - 1% of the epidermal cells in the skin of mice are gd T cells. • - gd TCR-CD3 (+), Thy-1 (+), CD4 (-), CD8 (-) • intestinal intraepithelial lymphocytes (iIELs): • - gd TCR-CD3 (+), Thy-1 (+), CD8 (+)

50. Tissue gd T cells • - gd T cells in epithelial tissues appear not to circulate • and remain fixed in the tissue sites. • The gd T cells in different epithelial tissue sites • appear to express different Vg and Vd gene segments • with limited diversity. • This selective expression of different V gene • segments in different epithelial tissues may reflect a • specialization of these T cells to respond to certain • types of Ags that tend to be found at these sites.