Fine tuning of TCR signaling by CD5

Current data indicate that CD5 functions as an inhibitor of TCR signal tran sduction. Consistent with this role, thymocyte selection in TCR transgenic/ CD5(-/-) mice is altered in a manner suggestive of enhanced TCR signaling. However, the impact of CD5 deletion on thymocyte selection varies depending on the transgenic TCR analyzed, ranging from a slight to a marked shift fr om positive toward negative selection. An explanation for the variable effe ct of CD5 on selection is suggested by the observation that CD5 surface exp ression is regulated by TCR signal intensity during development and CD5 sur face levels on mature thymocytes and T cells parallel the avidity of the po sitively selecting TCR/MHC/ligand interaction. In this study, we generated mice that overexpress CD5 during thymocyte development (CD5-tg), and then e xamined the effect of CD5 overexpression or CD5 deletion (CD5(-/-)) on sele ction of thymocytes that express the same TCR transgenes. The results demon strate that the effect on thymocyte selection of altering CD5 expression de pends on the avidity of the selecting interaction and, consequently, the le vel of basal (endogenous) CD5 surface expression. Substitution of endogenou s CD5 with a transgene encoding a truncated form of the protein failed to r escue the CD5(-/-) phenotype, demonstrating that the cytoplasmic domain of CD5 is required for its inhibitory function. Together, these results indica te that inducible regulation of CD5 surface expression during thymocyte sel ection functions to fine tune the TCR signaling response.