title: Distinct roles of Cdc42 in thymopoiesis and effector and memory T cell differentiation.
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.
authors: Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, Ohio, United States of America. fukun.guo@cchmc.org
authors: Fukun
authors: F
authors: Guo
authors: Shuangmin
authors: S
authors: Zhang
authors: Pulak
authors: P
authors: Tripathi
authors: Jochen
authors: J
authors: Mattner
authors: James
authors: J
authors: Phelan
authors: Alyssa
authors: A
authors: Sproles
authors: Jun
authors: J
authors: Mo
authors: Marsha
authors: M
authors: Wills-Karp
authors: H Leighton
authors: HL
authors: Grimes
authors: David
authors: D
authors: Hildeman
authors: Yi
authors: Y
authors: Zheng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D005434:Flow Cytometry; D015151:Immunoblotting; D051379:Mice; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000502:physiology*
chemical_list: D020764:cdc42 GTP-Binding Protein