Cutting edge: Rac GTPases sensitize activated T cells to die via Fas

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

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6384-6388
Number of pages5
JournalJournal of Immunology
Volume179
Issue number10
DOIs
StatePublished - Nov 15 2007

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Ramaswamy, M., Dumont, C., Cruz, A. C., Muppidi, J. R., Gomez, T. S., Billadeau, D. D., Tybulewicz, V. L. J., & Siegel, R. M. (2007). Cutting edge: Rac GTPases sensitize activated T cells to die via Fas. Journal of Immunology, 179(10), 6384-6388. https://doi.org/10.4049/jimmunol.179.10.6384