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Cutting Edge: Rac GTPases Sensitize Activated T Cells to Die via Fas¹

Madhu Ramaswamy^*, Celine Dumont, Anthony C. Cruz^*, Jagan R. Muppidi^*, Timothy S. Gomez, Daniel D. Billadeau, Victor L. J. Tybulewicz and Richard M. Siegel^2,*

^* Immunoregulation Unit, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; Division of Immune Cell Biology, National Institute for Medical Research, Mill Hill, London, United Kingdom; and Department of Oncology Research, Mayo Clinic, Rochester, MN 55905

In activated CD4⁺ T cells, TCR restimulation triggers apoptosis that depends on interactions between the death receptor Fas and its ligand, FasL. This process, termed restimulation-induced cell death (RICD), is a mechanism of peripheral immune tolerance. TCR signaling sensitizes activated T cells to Fas-mediated apoptosis, but what pathways mediate this process are not known. In this study we identify the Rho GTPases Rac1 and Rac2 as essential components in restimulation-induced cell death. RNA interference-mediated knockdown of Rac GTPases greatly reduced Fas-dependent, TCR-induced apoptosis. The ability of Rac1 to sensitize T cells to Fas-induced apoptosis correlated with Rac-mediated cytoskeletal reorganization, dephosphorylation of the ERM (ezrin/radixin/moesin) family of cytoskeletal linker proteins, and the translocation of Fas to lipid raft microdomains. In primary activated CD4⁺ T cells, Rac1 and Rac2 were independently required for maximal TCR-induced apoptosis. Activating Rac signaling may be a novel way to sensitize chronically stimulated lymphocytes to Fas-induced apoptosis, an important goal in the treatment of autoimmune diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported in part by the Intramural Research Program of National Institute of Arthritis and Musculoskeletal and Skin Diseases.

² To whom correspondence should be addressed: Dr. Richard M. Siegel, Building 10, Room 9N238, Bethesda, MD 20892. E-mail address: rsiegel{at}nih.gov

³ Abbreviations used in this paper: FasL, Fas ligand; ERM, ezrin/radixin/moesin; J.Vav1, Vav1-deficient Jurkat; RICD, restimulation-induced cell death; siRNA, small interfering RNA; WT, wild type.

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