%0 Journal Article
%T Distinct Roles of Cdc42 in Thymopoiesis and Effector and Memory T Cell Differentiation
%A Fukun Guo
%A Shuangmin Zhang
%A Pulak Tripathi
%A Jochen Mattner
%A James Phelan
%A Alyssa Sproles
%A Jun Mo
%A Marsha Wills-Karp
%A H. Leighton Grimes
%A David Hildeman
%A Yi Zheng
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0018002
%X Cdc42 of the Rho GTPase family has been implicated in cell actin organization, proliferation, survival, and migration but its physiological role is likely cell-type specific. By a T cell-specific deletion of Cdc42 in mouse, we have recently shown that Cdc42 maintains na£¿ve T cell homeostasis through promoting cell survival and suppressing T cell activation. Here we have further investigated the involvement of Cdc42 in multiple stages of T cell differentiation. We found that in Cdc42£¿/£¿ thymus, positive selection of CD4+CD8+ double-positive thymocytes was defective, CD4+ and CD8+ single-positive thymocytes were impaired in migration and showed an increase in cell apoptosis triggered by anti-CD3/-CD28 antibodies, and thymocytes were hyporesponsive to anti-CD3/-CD28-induced cell proliferation and hyperresponsive to anti-CD3/-CD28-stimulated MAP kinase activation. At the periphery, Cdc42-deficient naive T cells displayed an impaired actin polymerization and TCR clustering during the formation of mature immunological synapse, and showed an enhanced differentiation to Th1 and CD8+ effector and memory cells in vitro and in vivo. Finally, Cdc42£¿/£¿ mice exhibited exacerbated liver damage in an induced autoimmune disease model. Collectively, these data establish that Cdc42 is critically involved in thymopoiesis and plays a restrictive role in effector and memory T cell differentiation and autoimmunity.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0018002