Abstract
Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an important regulator of T cell homeostasis. Ligation of this receptor leads to prominent downregulation of T cell proliferation, mainly as a consequence of interference with IL-2 production. We here report that CTLA-4 engagement strikingly selectively shuts off activation of downstream T cell receptor (TCR)/CD28 signaling events, i.e., activation of the microtubule-associated protein kinase (MAPKs) ERK and JNK. In sharp contrast, proximal TCR signaling events such as ZAP70 and TCR-zeta chain phosphorylation are not affected by CTLA-4 engagement on activated T cells. Since activation of the ERK and JNK kinases is required for stimulation of interleukin (IL)-2 transcription, these data provide a molecular explanation for the block in IL-2 production imposed by CTLA-4.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Abatacept
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Animals
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Antigens, CD
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Antigens, Differentiation / metabolism
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Antigens, Differentiation / physiology*
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CTLA-4 Antigen
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Calcium-Calmodulin-Dependent Protein Kinases / immunology
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Enzyme Activation / immunology
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Immunoconjugates*
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Interleukin-2 / genetics
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JNK Mitogen-Activated Protein Kinases
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Membrane Proteins / immunology
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Membrane Proteins / metabolism*
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Mice
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Mice, Inbred C57BL
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Mitogen-Activated Protein Kinases*
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Phosphorylation
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Protein-Tyrosine Kinases / immunology
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Protein-Tyrosine Kinases / metabolism*
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism*
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T-Lymphocytes, Cytotoxic / immunology*
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Transcription, Genetic / immunology
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ZAP-70 Protein-Tyrosine Kinase
Substances
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Antigens, CD
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Antigens, Differentiation
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CTLA-4 Antigen
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Ctla4 protein, mouse
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Immunoconjugates
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Interleukin-2
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Membrane Proteins
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Receptors, Antigen, T-Cell
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antigen T cell receptor, zeta chain
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Abatacept
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Protein-Tyrosine Kinases
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ZAP-70 Protein-Tyrosine Kinase
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Zap70 protein, mouse
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases