Abstract
Anergy is a state of immunologic tolerance in which T cells are viable but incapable of responding to antigenic stimulation. Recent data indicate that anergic cells have a distinct gene expression program that determines their unique function. In this study we show that anergic human T cells selectively express the small GTPase ADP-ribosylation factor-6 (ARF6), which is involved in membrane traffic and regulation of the cortical actin cytoskeleton. ARF6 was expressed in the GTP-bound form that localizes at the plasma membrane, resulting in a distinct morphologic appearance of anergic cells. Forced expression of ARF6-GTP in Jurkat T cells prevented TCR-mediated reorganization of cortical actin, extracellular signal-regulated kinase1/2 activation, and IL-2 transcription. Forced expression of ARF6-GTP in primary human T cells inhibited extracellular signal-regulated kinase1/2 activation and proliferative responses. Importantly, T cells with the distribution pattern of ARF6-GTP were detected in peripheral blood, suggesting that anergic T cells may constitutively exist in vivo.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ADP-Ribosylation Factor 6
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ADP-Ribosylation Factors / biosynthesis
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ADP-Ribosylation Factors / blood
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ADP-Ribosylation Factors / metabolism*
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ADP-Ribosylation Factors / physiology*
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Actins / antagonists & inhibitors
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Actins / metabolism
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Biomarkers / analysis
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Cell Membrane / genetics
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Cell Membrane / immunology
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Cell Membrane / metabolism
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Clonal Anergy / genetics
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Clonal Anergy / immunology*
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Clone Cells
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Enzyme Activation / genetics
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Enzyme Activation / immunology
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Genetic Vectors
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Guanosine Triphosphate / genetics
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Guanosine Triphosphate / metabolism
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Humans
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / genetics
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Interleukin-2 / metabolism
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Jurkat Cells
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Membrane Proteins / blood
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Protein Binding / genetics
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Protein Binding / immunology
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RNA, Messenger / biosynthesis
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Receptors, Antigen, T-Cell / antagonists & inhibitors
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Receptors, Antigen, T-Cell / physiology
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T-Lymphocyte Subsets / enzymology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism*
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Transcription, Genetic / immunology
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Transfection
Substances
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ADP-Ribosylation Factor 6
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Actins
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Biomarkers
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Interleukin-2
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Membrane Proteins
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RNA, Messenger
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Receptors, Antigen, T-Cell
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Guanosine Triphosphate
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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ADP-Ribosylation Factors
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ARF6 protein, human