Cross-linking of CD80 on CD4+ T cells activates a calcium-dependent signaling pathway

CD80 expressed on the surface of APCs provides a positive costimulatory signal to naive CD4+ T cells via CD28 during activation. However, CD80 is also expressed on the surface of activated CD4+ T cells, and cross-linking CD80 on the surface of CD4+ T cells activated in the presence of Th1-promoting cytokines induces a direct up-regulation of T-bet, IFN-gamma, and Bcl(XL) expression in primary CD4+ T cells. The present data show that naive CD4+ T cells activated in Th1-promoting conditions in the presence of anti-CD80 mAb increase the level of IFN-gamma produced by increasing the rate of IFN-gamma mRNA transcription, which is supported by an increase in the level of T-bet phosphorylation and T-bet binding to the third intronic enhancer in the IFN-gamma locus. Furthermore, anti-CD80 mAb-induced increase in IFN-gamma expression and T-bet phosphorylation is dependent upon the activation of a Ca2+-dependent pathway as shown by anti-CD80 mAb-induced intracellular Ca2+ flux following CD80 cross-linking. These findings indicate a novel regulatory role for CD80-mediated intracellular signals in CD4+ T cells and have important implications for disease therapies using anti-costimulatory mAbs as use of an intact CD80 mAb may lead to CD80 cross-linking on activated T cells and enhanced proinflammatory cytokine production.