The molecular mechanism of TCR repertoire generation and coreceptor expression

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To study molecular mechanism of positive selection (PS) process for generating TCR repertoire, we analyzed related molecules for regulating expression of TCR and CD4 and_CD8 co-receptor. In use of gene manipulating mice, we proved followings.(1) TCR expression which increased randomly at DP stage was down-regulated without PS by TCR-MHC interaction but maintained its density without an appropriate TCR mediated signal. This conclusion is not consistent with the previous hypothesis that TCR expression on DP cells is originally low but it is induced to raise up when DP cells receive TCR mediated PS signal while TCR expression is not increased without TCR signal. However, our findings is helpful to resolve the question raised in the previous hypothesis how low TCR can recognize MHC molecules with low avidity which may positively select DP cells, resulting in DP cells activation for high TCR expression. (2) CD45 on DP cells was closely involved in down-regulation of TCR expression, which was overcome by TCR mediated signal. (3) We explored to detect tyrosine phosphorylation of intracellular substrates of thymocytes in the in vivo condition, and demonstrated that ZAP-70 is highly phosphorylated in PS process for CD8SP generation but not for CD4SP cell lineage. This result is consistent with the recent observation reported in a human patient possessing with abnormal ZAP-70, in which CD8SP cells did not develop but CD4SP cells were found though their number was small. These findings suggest an asymmetric mechanism for down regulation of CD4 and CD8 in DP thymocytes. (4) CD4 mature T cells are induced further functional development into Th1 and Th2 cells by non-MHC related regulation.