Cutting edge: Rac GTPases sensitize activated T cells to die via Fas.
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.
Ramaswamy
Madhu
M
Immunoregulation Unit, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Dumont
Celine
C
Cruz
Anthony C
AC
Muppidi
Jagan R
JR
Gomez
Timothy S
TS
Billadeau
Daniel D
DD
Tybulewicz
Victor L J
VL
Siegel
Richard M
RM
D017209:Apoptosis / Q000276:immunology*; D001327:Autoimmune Diseases / Q000201:enzymology / Q000276:immunology / Q000628:therapy; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D016923:Cell Death / Q000276:immunology; D003598:Cytoskeletal Proteins / Q000276:immunology / Q000378:metabolism; D003599:Cytoskeleton / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D053222:Fas Ligand Protein; D006801:Humans; D007108:Immune Tolerance; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D021962:Membrane Microdomains / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D008840:Microfilament Proteins / Q000276:immunology / Q000378:metabolism; D021381:Protein Transport / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D019014:fas Receptor / Q000276:immunology* / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000276:immunology* / Q000378:metabolism; D000097766:RAC2 GTP-Binding Protein; D000099149:Ezrin
D003598:Cytoskeletal Proteins; D053222:Fas Ligand Protein; D008565:Membrane Proteins; D008840:Microfilament Proteins; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; D000099149:Ezrin; C107953:RAC1 protein, human; C071058:moesin; C071776:radixin