Abstract
CTLA-4 is an important inhibitor of T cell activation. We used Jurkat cells expressing mutants of murine CTLA-4 to study the structural requirements for inhibitory signaling. We find that signals for the inhibition of IL-2 secretion are delivered efficiently by a CTLA-4 mutant in which both cytoplasmic tyrosines have been replaced by phenylalanines. A CTLA-4 mutant that lacks the carboxyl-terminal half of the intracellular domain also retains the ability to inhibit, but deletion of an additional 11 aa completely abrogates that capability. We conclude that delivery of an inhibitory signal requires the membrane-proximal region of the CTLA-4 cytoplasmic domain and does not depend upon the tyrosine phosphorylation of CTLA-4.
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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Abatacept
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Amino Acid Motifs / genetics
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Amino Acid Motifs / immunology
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Animals
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Antibodies, Monoclonal / metabolism
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Antigens, CD
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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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CD28 Antigens / physiology
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CD3 Complex / physiology
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CTLA-4 Antigen
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Cytoplasm / genetics
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Humans
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Immunoconjugates*
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Immunosuppressive Agents / pharmacology*
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / biosynthesis
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Jurkat Cells
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Lymphocyte Activation
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Mice
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Sequence Deletion
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Signal Transduction / genetics
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Signal Transduction / immunology*
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T-Lymphocytes / metabolism
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Tyrosine / genetics
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Tyrosine / physiology*
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Antigens, Differentiation
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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, human
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Ctla4 protein, mouse
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Immunoconjugates
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Immunosuppressive Agents
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Interleukin-2
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Tyrosine
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Abatacept