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

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

Fig 3.12 p106

Note: Predictions – Not real numbers !

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”

Fig. 7.2 The development of T cells.

How we know the thymus is important for T cell development 1.Thymectomy (removal of the thymus) in newborn animals results in the absence of T cells 2.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 3.Studies in mutant mice - the nude (nu/nu) mouse

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

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 ICD8 T cell Bind to self MHC alive bind to MHC class IICD4 T cell Do not bind self MHCApoptosis MHC – Major Histocompatibilty Complex Thymic cortical epithelial cells

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

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

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

Model to resolve alloreactivity paradox

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

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