Abstract
CTLA-4 (CD152) engagement results in down-regulation of T cell activation. Two mechanisms have been postulated to explain CTLA-4 inhibition of T cell activation: negative signaling and competitive antagonism of CD28:B7-mediated costimulation. We assessed the contributions of these two mechanisms using a panel of T cell lines expressing human CTLA-4 with mutations in the cytoplasmic region. Under conditions of B7-independent costimulation, inhibition of IL-2 production following CTLA-4 engagement required the CTLA-4 cytoplasmic region. In contrast, under B7-dependent costimulation, inhibition of IL-2 production by CTLA-4 engagement was directly proportional to CTLA-4 cell surface levels and did not require its cytoplasmic region. Thus, CTLA-4 down-regulates T cell activation by two different mechanisms-delivery of a negative signal or B7 sequestration-that are operational depending on the levels of CTLA-4 surface expression. These two mechanisms may have distinct functional outcomes: rapid inhibition of T cell activation or induction of T cell anergy.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Abatacept
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Amino Acid Sequence
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Antibodies, Monoclonal / pharmacology
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Antigens, CD / immunology
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Antigens, Differentiation / biosynthesis*
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Antigens, Differentiation / genetics
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Antigens, Differentiation / immunology*
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Antigens, Differentiation / physiology
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B7-1 Antigen / physiology
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B7-2 Antigen
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CD28 Antigens / immunology
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CD3 Complex / immunology
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CTLA-4 Antigen
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Cell Membrane / immunology
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Cell Membrane / metabolism
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Cytoplasm / immunology
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Down-Regulation / immunology
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Doxycycline / pharmacology
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Humans
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Immunoconjugates*
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Immunoglobulin Fc Fragments / genetics
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Immunoglobulin Fc Fragments / physiology
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Immunosuppressive Agents / pharmacology*
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Interleukin-2 / biosynthesis
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Jurkat Cells
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology*
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Membrane Glycoproteins / immunology
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Microspheres
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Molecular Sequence Data
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Peptide Fragments / immunology
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Recombinant Fusion Proteins / immunology
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Recombinant Fusion Proteins / pharmacology
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Signal Transduction / immunology
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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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B7-2 Antigen
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CD28 Antigens
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CD3 Complex
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CD86 protein, human
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CTLA-4 Antigen
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CTLA4 protein, human
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Immunoconjugates
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Immunoglobulin Fc Fragments
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Immunosuppressive Agents
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Interleukin-2
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Membrane Glycoproteins
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Peptide Fragments
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Recombinant Fusion Proteins
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Abatacept
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Doxycycline