Abstract
CTLA-4 engagement by mAbs inhibits, while CD28 enhances, IL-2 production and proliferation upon T cell activation. Here, we have analyzed the mechanisms involved in CTLA-4-mediated inhibition of T cell activation of naive CD4+ T cells using Ab cross-linking. CTLA-4 ligation inhibited CD3/CD28-induced IL-2 mRNA accumulation by inhibiting IL-2 transcription, which appears to be mediated in part through decreasing NF-AT accumulation in the nuclei. However, CTLA-4 ligation did not appear to affect the CD28-mediated stabilization of IL-2 mRNA. Further, CTLA-4 engagement inhibited progression through the cell cycle by inhibiting the production of cyclin D3, cyclin-dependent kinase (cdk)4, and cdk6 when the T cells were stimulated with anti-CD3/CD28 and with anti-CD3 alone. These results indicate that CTLA-4 signaling inhibits events early in T cell activation both at IL-2 transcription and at the level of IL-2-independent events of the cell cycle, and does not simply oppose CD28-mediated costimulation.
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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Animals
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Antigens, CD
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Antigens, Differentiation / metabolism*
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Biological Transport
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CD28 Antigens / metabolism
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CD3 Complex / metabolism
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CD4-Positive T-Lymphocytes / immunology*
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CTLA-4 Antigen
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Cell Cycle
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Cell Cycle Proteins / metabolism
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Cyclin D3
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / metabolism
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Cyclins
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DNA-Binding Proteins / metabolism
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Genes, Reporter
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Humans
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Immunoconjugates*
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Immunosuppressive Agents / metabolism*
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Interleukin-2 / biosynthesis
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Lymphocyte Activation*
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Mice
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Mice, Transgenic
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Microtubule-Associated Proteins / metabolism
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NFATC Transcription Factors
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Nuclear Proteins*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins*
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RNA, Messenger / isolation & purification
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S-Phase Kinase-Associated Proteins
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Transcription Factors / metabolism
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Transcription, Genetic
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Tumor Suppressor Proteins*
Substances
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Antigens, CD
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Antigens, Differentiation
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CCND3 protein, human
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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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Ccnd3 protein, mouse
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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Ctla4 protein, mouse
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Cyclin D3
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Cyclins
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DNA-Binding Proteins
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Immunoconjugates
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Immunosuppressive Agents
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Interleukin-2
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Microtubule-Associated Proteins
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NFATC Transcription Factors
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Nuclear Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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S-Phase Kinase-Associated Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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Abatacept
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Protein Serine-Threonine Kinases
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CDK4 protein, human
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CDK6 protein, human
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Cdk4 protein, mouse
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Cdk6 protein, mouse
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6
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Cyclin-Dependent Kinases