CD8 AND T CELL ACTIVATION AND THYMIC SELECTION

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The TCR/CD3 complex is a multimeric complex composed of molecules which are responsible for antigen binding signal transduction. Recent evidence suggest that on T cells interacting with antigen presenting cells, the CD8 or CD4 molecules become associated with this complex. The CD8 and CD4 molecules are associated with a protein tyrosine kinase, p56lck, thus on activated T cells CD8 or CD4 may mediate signalling through the TCR/CD3 complex. A number of systems have been developed to investigate the role of CD8, or other molecules, in T cell recognition and activation. Many of these systems have relied upon treatment with antibodies to CD8 to mimic the effect of binding physiologic ligand. We feel that a more ideal system to investigate the role of CD8 is a physiological situation in which the only variable is CD8 engagement. Through our recent studies which identified the region on MHC class I molecules which interacts with CD8, we have established a system to examine the contribution of CD8 to T cell activation upon interaction with physiologic ligand on antigen presenting cells. A comparative analysis of the response of the same T cell clone to interaction with APC's expressing either the wild type or mutant molecule will allow us to define the contribution of Cd8 mediated signal transduction to T cell activation. We will analyze T cell activation in this system by using measurable parameters indicative of the activation of the PtdInsP2 hydrolysis pathway; protein tyrosine kinase activity; and receptor redistribution, and correlate these events with induction of effector function in the T cell. Furthermore, the derivation of transgenic mouse lines which express either the wild type or mutant class I molecule will enable us to examine the role of CD8 in thymic selection events. We feel that these studies constitute a powerful approach to define the role of CD8 mediated signal transduction in activation of T cells at different stages of differentiation.