CMV peptide/ class I MHC complex (not the donor graft antigens). When in the face of the immunosuppressive effects of antirejection drugs CMV begins to replicate in the recipient, the infused cytotoxic T cells would attack the virally infected cells. Because mature, clonally expanded CTL are used, the lack of IL-2 needed for differentiation of the pCTL to CTL (see above) does not impair the killing of virally infected cells. (One of the effects of immunosuppression with the commonly used agent, cyclosporin A, is to decrease IL-2 production).

Model of Signal Transduction in T-cell Activation

Role of TCR and the CD3 complex

The TCR is comprised of a/p polypeptides complexed with the CD3 invariant chains, each having distinct roles in T-cell activation. Whereas the a/p polypeptides represent the antigen recognition moiety, CD3 serves to link these polypeptides to signaling pathways. An emerging model of T-cell activation suggests that one of the earliest events following antigen/MHC interaction with the TCR, and high affinity conjugate formation of the T cell with an antigen presenting cell, is the activation (by CD45 mediated dephosphorylation) of src family kinases, lck and fyn. Subsequently, these kinases are auto/trans phosphorylated, as are other substrates, including the tyrosine residues in the ITAM (immunoreceptor tyrosine based activation motif) of the CD3 molecules. ITAM (sequence: YxxL/ IxxxxxxxYxxL/l where Y is tyrosine, x any amino acid, L, leucine, and l is isoleu-cine) motifs represent sequences of amino acids containing two strategically located tyrosine residues, whose phosphorylation confers "docking" properties for proteins with SH2 (Src homology 2) domains (Fig. 9.8). The collection of proteins recruited to CD3 serve as the focal points for the construction of a molecular scaffold that links the TCR to signaling pathways.

Role of phosphorylated ITAMs in linking TCR to signaling pathways

Tyrosine phosphorylated ITAMs serve as docking sites for src family kinases, the ZAP 70 tyrosine kinase, and some adapter molecules. All of these molecules bind to phosphorylated ITAMs via their SH2 domains. Based on in vitro studies of ZAP 70 kinase substrates, it is proposed that phospholipase Cy (PL-Cy) is activated by ZAP 70 mediated phosphorylation. PL-Cy hydrolyzes phos-phatidylinositol bisphosphate (PIP2) whose products, inositol trisphosphate and diacylglycerol, bind to their respective receptors, initiating distinct biochemical changes that lead to increases in the concentration of cytosolic calcium and activation of protein kinase C, respectively. Many of the adapter proteins that bind to phosphorylated ITAMS also possess an SH3 domain. SH3 domains recognize and bind to motifs bearing proline residues. Proteins that possess both SH2 and SH3 domains can function in protein/protein interactions because binding of one "face" to ITAMs still allows for binding to proline rich proteins that directly, or indirectly, link the TCR to signaling molecules. As an example, one adapter molecule binds a guanine exchange protein (GEF) that activates p21 ras by exchanging the bound GDP for GTP. Ras (p21) is known to mediate signaling events that

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book

Post a comment