Recent genetic evidence suggests that CD5 may influence signals originating from the T cell receptor during positive and negative selection. Homozygosity of a null mutation of CD5 causes thymocytes to become hyper-responsive to TCR engagement and results in abnormal development of T cells. The mechanism by which CD5 mediates this effect is not understood, nor is it clear why the hyper-responsiveness is confined to thymocytes and does not affect mature peripheral T cells. The overall goal of this proposal is to explore in detail the physiological function of CD5 and thereby contribute to a better understanding of TCR signal transduction during lymphocyte development. This goal will be addressed by expressing mutant form of the CD5 molecule both in vivo by means of transgenesis and in vitro through transfections into a CD5 deficient cell line. Parallel studies will include the isolation and identification of thymocyte- specific proteins that may interact with the cytoplasmic tail of CD5. The relevant biological impact of the CD5null phenotype will be assessed by a detailed study of the TCR repertoire in CD5null mice and a careful examination of cytokine patterns after CD5null mice have been challenged in vivo with nominal antigens. Taken together these studies will assess how the absence of a negative regulator of TCR signal transduction may affect generation of the TCR repertoire.
