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. 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.

51. Ligands Recognized by gd T Cells: - Elusive (令人困惑的)
- Some gd T cells may bind directly to a protein Ag
without requiring Ag processing and presentation
together with MHC.
Function of gd T Cells:
- Not clear
- Some gd T cells may be uniquely suited to respond
to heat-shock proteins and may have evolved to
eliminate damaged cells as well as microbial invaders.

52. The End