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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.