V a -J a

1. Va-Ja

4. T Cell Maturation in the Thymus Positive selection: permits the survival of only those T cells whose TCRs are capable of recognizing self-MHC molecule. MHC restriction Negative selection: eliminates T cells that react too strongly with self-MHC plus self-peptide. Self tolerance ~98% of thymocytes die by apoptosis

5. Role of Thymus in Selection of T Cell Repertoire Zinkernagel et al.

9. +

10. The TCR-MHC Interaction is Required for Positive Selection

11. Evidence for Negative Selection: self antigen plus MHC are required

12. Hypotheses to explain the MHC-depedent positive and negative selection • Avidity hypothesis: the outcome of MHC-peptide binding by TCR depends on the strength of the signal delivered by the receptor on binding, and this will, in turn, depend on both the affinity of the TCR for MHC-peptide complex and the density of the complex on thymic epithelial cells. • Differential-signaling hypothesis: the signals leading to positive and negative selection are different.

14. leads to positive selection leads to negative selection

15. How a double positive precursor become CD4+ or CD8+ cells? • Instructive model: the interaction between TCR, CD8, CD4, and MHC class I or class II instruct a cell to differentiate into either CD8+ or CD4+ cells. • Stochastic model: CD4 or CD8 expression is switched off randomly.

22. The initiation of TCR signaling

23. Ca2+ PKC SLP-76

26. Two signals are necessary for full T cell activation: • Signal 1: generated by interaction of MHC-peptide with the TCR-CD3 complex • Signal 2: generated by interaction of CD28 on the T cells and members of the B7 family on the APC

27. Co-stimulatory signals are required for full T cell activation Expressed on resting and activated T cells Expressed on dendritic cells activated macrophages and activated B cells Expressed on activated T cells

28. CTLA-4Ig as a chimeric suppressor of co-stimulation

29. Lack of co-stimulatory signal results in clonal anergy

30. Lack of co-stimulatory signal results in clonal anergy

34. Superantigens: proteins that bind simultaneously to TCR Vb chain and a chain of MHC class II. Superantigens induce T cell activation and proliferation.

35. Exogenous superantigens are mainly exotoxins secreted by gram- positive bacteria

36. Endogenous Superantigens: cell-membrane proteins encoded by certain viruses that infect mammalian cells. • The activation by superantigens is polyclonal. • The massive activation by superantigens results in overproduction of T helper cell cytokines, leading to systemic toxicity.

37. Activation of T helper cells

38. Naïve T cells: cells never meet antigens before. They can only be activated by dendritic cells. • Effector cells: short-lived cells with special functions such as cytokine secretion and B-cell help and cytotoxic killing activity. Effector cells are derived from naïve or memory cells after antigen activation. TH1 and TH2 subsets. • Memory cells: long-lived resting cells that are derived from naïve and effector cells. They respond faster and stronger to a subsequent challenge with the same antigen. • CD4+CD25+ regulatory T cells: cells that can inhibit the proliferation of other T cell population in vitro and also inhibit the development of experimental autoimmune systems.

39. Comparison of different antigen-presenting cells

40. Two pathways to apoptosis in T cells Activation-induced cell death

41. Failure of apoptosis causes defective lymphocyte homeostasis Canale-Smith symdrome: fas+/- , elevated lymphocyte numbers, Hyper-gammaglobulinemia, Autoantibodies against RBC and platelets lpr/lpr mice:Fas mutant gld/gld mice: FasL mutant