Abstract
In lymphocytes, integration of Ca2+ and other signaling pathways results in productive activation, while unopposed Ca2+ signaling leads to tolerance or anergy. We show that the Ca2+-regulated transcription factor NFAT has an integral role in both aspects of lymphocyte function. Ca2+/calcineurin signaling induces a limited set of anergy-associated genes, distinct from genes induced in the productive immune response; these genes are upregulated in vivo in tolerant T cells and are largely NFAT dependent. T cells lacking NFAT1 are resistant to anergy induction; conversely, NFAT1 induces T cell anergy if prevented from interacting with its transcriptional partner AP-1 (Fos/Jun). Thus, in the absence of AP-1, NFAT imposes a genetic program of lymphocyte anergy that counters the program of productive activation mediated by the cooperative NFAT:AP-1 complex.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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CD28 Antigens / biosynthesis
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Calcineurin / metabolism
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Calcium / metabolism
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Cell Death
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Cell Division
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Chelating Agents / pharmacology
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Clonal Anergy
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Cytokines / metabolism
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DNA-Binding Proteins / metabolism
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Dose-Response Relationship, Drug
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Enzyme-Linked Immunosorbent Assay
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Immunoblotting
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Ionomycin / pharmacology
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Lymphocytes / metabolism*
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Mice
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Mice, Inbred BALB C
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Models, Biological
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NFATC Transcription Factors
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Nuclear Proteins*
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Retroviridae / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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T-Lymphocytes / metabolism
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Th1 Cells / metabolism
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Time Factors
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Transcription Factor AP-1 / metabolism
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Transcription Factors / metabolism
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Transcription, Genetic*
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Up-Regulation
Substances
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CD28 Antigens
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Chelating Agents
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Cytokines
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DNA-Binding Proteins
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NFATC Transcription Factors
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Nuclear Proteins
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Transcription Factor AP-1
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Transcription Factors
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Ionomycin
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Calcineurin
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Calcium