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IP₃ Receptor-Mediated Ca²⁺ Release in Naive CD4 T Cells Dictates Their Cytokine Program¹

Viswas K. Nagaleekar^*, Sean A. Diehl^*, Ignacio Juncadella, Colette Charland^*, Natarajan Muthusamy, Sheri Eaton, Laura Haynes, Lee Ann Garrett-Sinha^¶, Juan Anguita and Mercedes Rincón^2,*

^* Department of Medicine/Immunobiology Program, University of Vermont, Burlington, VT 05405; Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003; Division of Hematology and Oncology, Ohio State University, Columbus, OH 43210; Trudeau Institute, Saranac Lake, NY 12983; and ^¶ Department of Biochemistry, State University of New York, Buffalo, NY 14241

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 IP₃Rs and their role during the activation of CD4 T cells. In this study we show that mouse naive CD4 T cells express IP₃R1, IP₃R2, and IP₃R3, but that gene expression of IP₃R3 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- expression. Interestingly, while inhibition of IP₃R function early during activation blocks IL-2 and IFN- 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.

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¹ This work was supported by a National Institutes of Health Program Project Grant P02AI045666 (to M.R.) and the Centers of Biomedical Research Excellence Program of the National Center for Research Resources (RR15557) (to M.R.).

² Address correspondence and reprint requests to Dr. Mercedes Rincon, Department of Medicine/Immunobiology Program, Given Medical Building D-305, University of Vermont, Burlington, VT 05405. E-mail address: mrincon{at}uvm.edu

³ Abbreviations used in this paper: IP₃, inositol 1,4,5-trisphosphate; 2-APB, 2-aminoethoxydiphenyl borate; ChIP, chromatin immunoprecipitation; CRAC, Ca²⁺ release-activated Ca²⁺; IP₃R, IP₃ receptor; RPA, RNase protection assay; Xe-C, xestospongin C.