Introduction to C.M.I., the TCR, and T Cell Development

1. Introduction to C.M.I., the TCR, and T Cell Development Abbas Chapters 7,8 web

2. The T Cell Receptor • Highly analagous to Ig/BCR • TCR is an a/b dimer, both chains Ig superfamily members (a is like light chain, b is like heavy) • Diverse receptor repertoire generated by V(D)J recombination • Only membrane-bound form, no isotype switching • Associates with signaling complex: CD3

3. Fig 3.12 p106

5. Note: Predictions – Not real numbers!

8. T Cell Co-Receptors • TCR interaction with MHC/peptide is weak • Stabilized by accessory molecules: CD4 (MHC II) and CD8 (MHC I) • Peripheral T cells express one or the other, but not both • Correlate with function: CD4+ T cells are “helpers” and CD8+ T cells are “killers”

11. Fig. 7.2 The development of T cells.

13. How we know the thymus is important for T cell development Thymectomy (removal of the thymus) in newborn animals results in the absence of T cells Fetal thymic organ culture (FTOC) - bone marrow stem cells can be added to fetal thymi (used because they don’t have T cells in them yet) in vitro, and the resulting cell populations are similar to what is seen in a normal thymus Studies in mutant mice - the nude (nu/nu) mouse

15. Summary of T cell development • Precursors (double neg) seed thymus, proliferate for ~1 week (c-kit/IL-7 dependent) • Stop dividing, begin rearranging TCRb (D-J first, then V-DJ) • TCRb pairs with pre-Ta (non-polymorphic protein) to form pre-TCR; split with g/d lineage • Surface pre-TCR+CD3 signals to stop b rearrangement, initiates more proliferation, expression of CD4 and CD8 (double pos) • Stop dividing, begin rearranging TCRa • Surface expression of a/b TCR signals to stop a rearrange • Positive and negative selection, down-regulation of CD4 or CD8 to become single pos

16. POSITIVE SELECTION Self MHC restricted: (1) Rescue of double-positive thymocytes from programmed cell death (2) determine the expression of CD4 or CD8 coreceptor on mature T cells. bind to MHC class I CD8 T cell Bind to self MHC alive bind to MHC class II CD4 T cell Do not bind self MHC Apoptosis MHC – Major Histocompatibilty Complex Thymic cortical epithelial cells

17. NEGATIVE SELECTION Self tolerant: Thymocytes recognizing self peptide:self MHC complexes too well are induced to undergo apoptosis. Bind strongly to self MHC-self antigen Apoptosis Do not bind strongly to self MHC-self antigen Alive Bone marrow derived dendritic cells and macrophages

19. It is a paradox that recognition of self MHC:self peptide ligand by the same basic receptor can lead to two opposing effects, namely positive and negative selection. Avidity hypothesis Differential signaling hypothesis

20. The MHC Restriction Paradoxes Alloreactivity: ~1-10% of T cells react with MHC molecules of non-self haplotypes (this is the basis for tissue/organ graft rejection)

21. Model to resolve alloreactivity paradox

22. The MHC Restriction Paradoxes Alloreactivity: ~1-10% of T cells react with MHC molecules of non-self haplotypes (this is the basis for tissue/organ graft rejection) Superantigens: bacterial and viral proteins that can activate ~2-20% of all T cells (all T cells expressing a subset of Vb gene segments) - bacterial superantigens are responsible for toxic shock syndrome

23. staphylococcal enterotoxin (SE) Fig. 5.19 Superantigens bind directly to T-cell receptors and to MHC molecules.