One Path to Costimulation Is Through NFAT

Abstract

To be fully activated, T cells require ligation of both the T cell receptor (TCR) and a second receptor (CD28). Diehn et al. performed a global analysis of changes in gene expression in response to TCR activation alone or in the presence of costimulation through the CD28 receptor. One of the results from their analysis was that, for the majority of genes whose activity increased or repressed in response to TCR ligation, this response was simply amplified by CD28 costimulation. Many of the genes whose changes in expression (increased or decreased) were most amplified were targets of the nuclear factor of activated T cells (NFAT) transcription factors. NFAT is activated by dephosphorylation mediated by the phosphatase calcineurin and translocation into the nucleus. For many genes, inhibition of activation of calcineurin with FK506 eliminated the enhanced response produced by costimulation with a CD28 ligand and a TCR ligand. In costimulated cells, a larger proportion of the total NFAT was dephosphorylated compared with that in cells stimulated by TCR ligation alone. Furthermore, CD28 ligation, which is known to stimulate a phosphoinositide 3-kinase (PI3K) and Akt pathway, stimulated the phosphorylation of glycogen synthase kinase 3 (GSK3), inhibiting its activity. GSK3 may be one of the kinases responsible for phosphorylation of NFAT, which promotes its nuclear efflux. Thus, a key mechanism by which CD28 costimulation may enhance TCR-stimulated changes in gene expression may be by decreasing the nuclear efflux and promoting the activation of NFAT by inhibiting GSK3 and activation of calcineurin. M. Diehn, A. A. Alizadeh, O. J. Rando, C. L. Liu, K. Stankunas, D. Botstein, G. R. Crabtree, P. O. Brown, Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation. Proc. Natl. Acad. Sci. U.S.A. 99 , 11796-11801 (2002). [Abstract] [Full Text]