V-J

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

Zinkernagel et al.

Role of Thymus in Selection of T Cell Repertoire

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The TCR-MHC Interaction is Required for Positive Selection

Evidence for Negative Selection: self antigen plus MHC are required

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.

leads to positive selection

leads to negative selection

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.

The initiation of TCR signaling

SLP-76

Ca2+

PKC

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

Co-stimulatory signals are required for full T cell activation

Expressed on activated T cells

Expressed on dendritic cells activated macrophages andactivated B cells

Expressed on resting andactivated T cells

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

Lack of co-stimulatory signal results in clonal anergy

Lack of co-stimulatory signal results in clonal anergy

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

Exogenous superantigens are mainly exotoxins secreted by gram-positive bacteria

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.

Activation of T helper cells

• 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.

Comparison of different antigen-presenting cells

Two pathwaysto apoptosis inT cells

Activation-inducedcell death

Failure of apoptosis causes defective lymphocyte homeostasisCanale-Smith symdrome:fas+/- , elevated lymphocyte numbers,Hyper-gammaglobulinemia,Autoantibodies against RBC and platelets

lpr/lpr mice:Fas mutant gld/gld mice: FasL mutant