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

IP₃ (inositol 1,4,5-trisphosphate) receptors (IP₃Rs) regulate the release of Ca²⁺ from intracellular stores in response to IP₃. Little is known about regulation of the expression of IP ₃Rs and their role during the activation of CD4 T cells. In this study we show that mouse naive CD4 T cells express IP₃R1, IP ₃R2, and IP₃R3, but that gene expression of IP ₃R3 primarily is down-regulated upon activation due to loss of the Ets-1 transcription factor. Down-regulation of IP₃R expression in activated CD4 T cells is associated with the failure of TCR ligation to trigger Ca²⁺ release in these cells. We also show that down-regulation of specific IP₃Rs in activated CD4 T cells correlates with the requirement of IP₃R-mediated Ca²⁺ release only for the induction of, but not for the maintenance of, IL-2 and IFN-γ expression. Interestingly, while inhibition of IP₃R function early during activation blocks IL-2 and IFN-γ production, it promotes the production of IL-17 by CD4 T cells. Thus, IP₃Rs 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.