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- Title
Distinct Roles of Cdc42 in Thymopoiesis and Effector and Memory T Cell Differentiation.
- Authors
Fukun Guo; Shuangmin Zhang; Tripathi, Pulak; Mattner, Jochen; Phelan, James; Sproles, Alyssa; Jun Mo; Wills-Karp, Marsha; Grimes, H. Leighton; Hildeman, David; Yi Zheng
- Abstract
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 naïve 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.
- Publication
PLoS ONE, 2011, Vol 6, Issue 3, p1
- ISSN
1932-6203
- Publication type
Academic Journal
- DOI
10.1371/journal.pone.0018002