T Cell Maturation and Activation

1. T Cell Maturation and Activation February 15, 2001

2. Outline • T Cell Maturation • Early development in the thymus • Positive Selection and Negative Selection • CD4+ T Cells vs. CD8+ T Cells • T Cell Activation • Signal Transduction/Gene Expression • Costimulation • Expansion vs. Anergy

3. T Cell Maturation (Bone Marrow  Thymus  Periphery)

4. Fig. 10-2

5. Fig. 10-3

6. Fig. 10-5 Positive Selection And Negative Selection

8. Fig. 10-6 Positive Selection

9. Positive Selection

10. Fig. 10-8 Negative Selection

11. A Paradox….. • Positive Selection – Allows survival of thymocytes which recognize self-MHC. Other thymocytes die by apoptosis. ( Self-MHC restriction) • Negative Selection – Leads to apoptosis of thymocytes with high avidity for self-MHC, or with an avidity for self-MHC + self-Ag. ( Self Tolerance) Positive Selection  Negative Selection  No T Cells? • Clearly, not all thymocytes are deleted by apoptosis during negative selection, or we would not have any T cells.

12. Two Hypotheses….. • Avidity Hypothesis – High-avidity binding of TCR to MHC/Ag leads to apoptosis, but low-avidity binding leads to release from the thymus of mature T cells. • Differential Signaling Hypothesis – “Complete” signals through TCR by MHC/Ag lead to apoptosis, but “weak or partial” signals lead to release from the thymus of mature T cells. • Experimental data support some combination of both hypotheses

13. Fig. 10-9 CD4+ T Cells vs. CD8+ T Cells - 2 Models...

14. Outline • T Cell Maturation • Early development in the thymus • Positive Selection and Negative Selection • CD4+ T Cells vs. CD8+ T Cells • T Cell Activation • Signal Transduction/Gene Expression • Costimulation • Expansion vs. Anergy

15. T Cell Activation • Interaction of TCR/CD3 complex with MHC/Ag complex leads to activation signal(s) • This interaction also involves accessory or costimulatory molecules • Activation signals cause T cells to enter cell cycle • This involves activation of numerous genes

16. Signal Transduction • Receptor-Ligand Interactions • Second Messengers (cAMP, Ca2+, DAG, IP3) • Protein Kinases, Protein Phosphatases • G Proteins (GTP-binding proteins)

17. Fig. 10-12

19. Fig. 10-14 Costimulation

20. Clonal Expansion vs. Clonal Anergy • Clonal Expansion - Expansion/proliferation of a clone of T cells from a single, activated T cell • Clonal Anergy - Inactivation of a T cell • Interaction of TCR/CD3 with MHC/Ag can result in either expansion or anergy • This outcome is dependent on costimulation (w/costimulation  expansion; w/out costimulation  anergy)

21. Fig. 10-15