Analysis of thymocyte development reveals that the GTPase RhoA is a positive regulator of T cell receptor responses in vivo

Loss of function of the guanine nucleotide binding protein RhoA blocks pre- T cell differentiation and survival indicating that this GTPase is a critic al signaling molecule during early thymocyte development. Previous work has shown that the B-ho family GTPase Rac-1 can initiate changes in actin dyna mics necessary and sufficient for pre-T cell development. The present data now show that Rac-1 actions in pre-T cells require Rho function but that Rh oA cannot substitute for Rac-1 and induce the actin cytoskeletal changes ne cessary for pre-T cell development, Activation of Rho is thus not sufficien t to induce pre-T cell differentiation or survival in the absence of the pr e-T cell receptor (TCR). The failure of RhoA activation to impact on pre-TC R-mediated signaling was in marked contrast to its actions on T cell respon ses mediated by the mature TCR alpha/beta complex. Cells expressing active RhoA were thus hyperresponsive in he context of TCR-induced proliferation i n vitro and in vivo showed augmented positive selection of thymocytes expre ssing defined TCR complexes. This reveals that RhoA function is not only im portant for pre-T cells but also plays a role in determining the fate of ma ture T cells.