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Potent inhibition of NFAT activation and T cell cytokine production by novel low molecular weight pyrazole compounds 总被引:5,自引:0,他引:5
Trevillyan JM Chiou XG Chen YW Ballaron SJ Sheets MP Smith ML Wiedeman PE Warrior U Wilkins J Gubbins EJ Gagne GD Fagerland J Carter GW Luly JR Mollison KW Djuric SW 《The Journal of biological chemistry》2001,276(51):48118-48126
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Human endothelial cells (EC) express MHC class II molecules in vivo and are likely to be involved in presentation of antigens to CD4(+) T cells. We examined, at the single-cell level, EC presentation of superantigens to resting CD4(+) memory T cells. Within 2 h of adherence to class II+ EC early T cell activation is evidenced by translocation of nuclear factor of activated T cells (NFAT), surface expression of CD69, and synthesis of IFN-gamma and IL-2. Naive T cells are not activated. T cell activation is dependent on the prior induction of MHC class II molecules on EC and is blocked by antibodies to LFA-3 (CD58). Our data place EC along a spectrum of antigen-presenting ability. Activated B cells and macrophages trigger more cells to express cytokines than do EC and at lower antigen concentrations; EC are in turn, superior to fibroblasts or smooth muscle cells. Furthermore, the concept of activation thresholds for cytokine synthesis within T cells also extends to earlier activation events: NFAT translocation is relatively easy to trigger, as is CD69 expression; fewer cells can be triggered to express IFN-gamma and fewer still to express IL-2. EC may, therefore, contribute to a graded immune response by inducing qualitatively and quantitatively different responses than professional APC. 相似文献
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Anergy is an important mechanism of maintaining peripheral immune tolerance. T cells rendered anergic are refractory to further stimulation and are characterized by defective proliferation and IL-2 production. We used a model of in vivo anergy induction in murine CD8+ T cells to analyze the initial signaling events in anergic T cells. Tolerant T cells displayed reduced phospholipase Cgamma activation and calcium mobilization, indicating a defect in calcium signaling. This correlated with a block in nuclear localization of NFAT1 in anergic cells. However, we found that stimulation of anergic, but not naive T cells induced nuclear translocation of NFAT2. This suggested that NFAT2 is activated preferentially by reduced calcium signaling, and we confirmed this hypothesis by stimulating naive T cells under conditions of calcium limitation or partial calcineurin inhibition. Thus, our work provides new insight into how T cell stimulation conditions might dictate specific NFAT isoform activation and implicates NFAT2 involvement in the expression of anergy-related genes. 相似文献
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