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.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Apoptosis / immunology*
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Autoimmune Diseases / enzymology
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Autoimmune Diseases / immunology
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Autoimmune Diseases / therapy
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / enzymology
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CD4-Positive T-Lymphocytes / immunology*
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Cell Death / immunology
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Cytoskeletal Proteins / immunology
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Cytoskeletal Proteins / metabolism
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Cytoskeleton / immunology
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Cytoskeleton / metabolism
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Enzyme Activation / immunology
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Fas Ligand Protein
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Humans
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Immune Tolerance*
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Jurkat Cells
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Lymphocyte Activation / immunology*
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Membrane Microdomains / immunology
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Membrane Microdomains / metabolism
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Membrane Proteins / immunology
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Membrane Proteins / metabolism
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Microfilament Proteins / immunology
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Microfilament Proteins / metabolism
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Protein Transport / immunology
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RAC2 GTP-Binding Protein
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism
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Signal Transduction / immunology
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fas Receptor / immunology*
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fas Receptor / metabolism
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rac GTP-Binding Proteins / immunology*
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rac GTP-Binding Proteins / metabolism
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rac1 GTP-Binding Protein / immunology*
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rac1 GTP-Binding Protein / metabolism
Substances
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Cytoskeletal Proteins
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Fas Ligand Protein
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Membrane Proteins
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Microfilament Proteins
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RAC1 protein, human
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Receptors, Antigen, T-Cell
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ezrin
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fas Receptor
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moesin
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radixin
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rac GTP-Binding Proteins
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rac1 GTP-Binding Protein