T cell cytokine expression mediated by nuclear factor of activated T cells is selectively regulated through a new calcineurin binding region

Abstract

The nuclear factor of activated T cells (NFAT) family transcription factors, NFATc1-NFATc4, are implicated in various biological events including T cell cytokine expression. To elucidate the reason and mechanisms by which NFAT successfully obtained its functional diversity, comparative analyses among NFATcs as well as cytokines were performed in human T cells. Both NFATc1 and NFATc2 contributed to stimulation-induced expression of IL-2, though IL-4 and TNF-alpha expression was dominantly regulated by NFATc1 and NFATc2, respectively. The difference was caused, at least in part, by their distinct structures of C-terminal transactivation domains. Although the expression of NFATc4 in normal T cells was very scarce, cytokine expression was strongly suppressed by its augmented expression. The intramolecular regions of NFATcs responsible for interacting with calcineurin were comparatively investigated. In addition to clarifying the differential contribution of preexisting calcineurin-binding regions, CNBR1 and CNBR2, within the Ca2+ regulatory domain, we identified a new region, CNBR3, located between them. The interaction of calcineurin with NFATc1 and NFATc4 but not with other NFATcs was regulated by CNBR3. Accordingly, the introduction of NFATc1-CNBR3 in T cells alleviated the expression of IL-4 but not TNF-alpha. The characteristic features of NFAT members in the interaction with calcineurin may be useful to achieve selective regulation of T cell functions.