Abstract
Regulation of peripheral T cell responses is critical for preserving self tolerance. Memory T cells have a lower threshold for activation through the TCR and are thought to be less dependent on costimulation than naive T cells, suggesting a requirement for more stringent regulation of memory T cells. We have recently shown that CD4 engagement apart from the TCR results in the inactivation of memory, but not naive, CD4 T cells. We show here that this inhibition requires ligation of CTLA-4, in that blocking CTLA-4-B7 interactions restores memory CD4 T cell responsiveness. Early signaling through CTLA-4 is possible because resting memory, but not naive, CD4 T cells contain intracellular stores of CTLA-4 that are continuously recycled between the cytoplasm and the cell surface. This mechanism ensures that low intensity TCR engagements, which are thought to be important for peripheral T cell longevity, do not cause memory T cell activation but instead raise their threshold for costimulatory signals. This may give memory T cells an extended lifespan with a reduced risk of inappropriate activation.
Publication types
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Comparative Study
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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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Abatacept
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Animals
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Antibodies, Monoclonal / metabolism
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Antibodies, Monoclonal / pharmacology
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Antigen-Presenting Cells / immunology
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Antigen-Presenting Cells / metabolism
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Antigens, CD
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Antigens, Differentiation / biosynthesis
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Antigens, Differentiation / metabolism
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Antigens, Differentiation / physiology*
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B7-1 Antigen / biosynthesis
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B7-1 Antigen / pharmacology
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Binding Sites, Antibody
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CD28 Antigens / immunology
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CD28 Antigens / metabolism
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CD3 Complex / immunology
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology*
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CTLA-4 Antigen
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Cell Line
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Cell Membrane / immunology
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Cell Membrane / metabolism
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Cytoplasm / immunology
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Cytoplasm / metabolism
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Female
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Fibroblasts / immunology
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Fibroblasts / metabolism
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Histocompatibility Antigens Class II / biosynthesis
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Histocompatibility Antigens Class II / genetics
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Immune Tolerance / immunology
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Immunoconjugates*
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Immunologic Memory* / immunology
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Immunosuppressive Agents / pharmacology
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Intracellular Fluid / immunology
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Intracellular Fluid / metabolism
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Lymphocyte Activation / immunology*
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Mice
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Mice, Inbred BALB C
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Mice, Mutant Strains
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Receptors, Fc / metabolism
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Solubility
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology*
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Antigens, Differentiation
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B7-1 Antigen
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CD28 Antigens
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CD3 Complex
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CTLA-4 Antigen
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Ctla4 protein, mouse
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Histocompatibility Antigens Class II
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Immunoconjugates
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Immunosuppressive Agents
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Receptors, Fc
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Abatacept