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.

Gene Targeting RhoA Reveals Its Essential Role in Coordinating Mitochondrial Function and Thymocyte Development

“…The decreased numbers of SP thymocytes may not only result from defective β-selection, but also from impaired positive selection and/or lineage commitment. To examine positive selection in RhoA −/− mice, we analyzed DP, CD4 + SP and CD8 + SP thymocytes for the surface expression of CD69, upregulation of which is a critical marker of successful positive selection (34). We found that RhoA −/− mice had more CD69 hi CD4 + CD8 + , but less CD69 hi CD4 + and CD69 hi CD8 + , thymocytes than the WT control mice (Fig.…”

“…4A). To determine at which specific point DP thymocyte development was blocked in RhoA −/− mice, we analyzed the expression of TCRβ together with CD69 in total thymocytes (1, 34), by FACS. As shown in Fig.…”

Genome-wide association study of antibody response to Newcastle disease virus in chicken

“…In fact, SLIT/ROBO signaling can influence the expression of Rac1 and CDC42 [33]. Rac1 plays a crucial role in T cell development [34] while CDC42 is essential for memory T cell growth and differentiation [35,36]. Therefore, SLIT/ROBO signaling could contribute to adaptive immunity through Rac1 or/and CDC42.…”

Redundant and nonredundant roles for Cdc42 and Rac1 in lymphomas developed in NPM-ALK transgenic mice

“…[17][18][19] To achieve a T-cell-restricted deletion, we crossed conditional Cdc42 fl/fl or Rac1 fl/fl mice with CD4Cre mice that express the Cre recombinase in both CD4 and CD8 T cells under the control of the CD4 minimal promoter. 20 By using this approach, we aimed at deleting Cdc42 or Rac1 simultaneously with the induction of NPM-ALK expression, because NPM-ALK expression is under the control of the same CD4 promoter.…”