IP3 receptor-mediated Ca2+ release in naive CD4 T cells dictates their cytokine program.

IP(3) (inositol 1,4,5-trisphosphate) receptors (IP(3)Rs) regulate the release of Ca(2+) from intracellular stores in response to IP(3). Little is known about regulation of the expression of IP(3)Rs and their role during the activation of CD4 T cells. In this study we show that mouse naive CD4 T cells express IP(3)R1, IP(3)R2, and IP(3)R3, but that gene expression of IP(3)R3 primarily is down-regulated upon activation due to loss of the Ets-1 transcription factor. Down-regulation of IP(3)R expression in activated CD4 T cells is associated with the failure of TCR ligation to trigger Ca(2+) release in these cells. We also show that down-regulation of specific IP(3)Rs in activated CD4 T cells correlates with the requirement of IP(3)R-mediated Ca(2+) release only for the induction of, but not for the maintenance of, IL-2 and IFN-gamma expression. Interestingly, while inhibition of IP(3)R function early during activation blocks IL-2 and IFN-gamma production, it promotes the production of IL-17 by CD4 T cells. Thus, IP(3)Rs play a key role in the activation and differentiation of CD4 T cells. The immunosuppressive effect of pharmacological blockers of these receptors may be complicated by promoting the development of inflammatory CD4 T cells.