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.
Nagaleekar
Viswas K
VK
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, VT 05405, USA.
Diehl
Sean A
SA
Juncadella
Ignacio
I
Charland
Colette
C
Muthusamy
Natarajan
N
Eaton
Sheri
S
Haynes
Laura
L
Garrett-Sinha
Lee Ann
LA
Anguita
Juan
J
Rincón
Mercedes
M
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050784:Proto-Oncogene Protein c-ets-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000502:physiology; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology
D016207:Cytokines; C494042:Ets1 protein, mouse; D053496:Inositol 1,4,5-Trisphosphate Receptors; D050784:Proto-Oncogene Protein c-ets-1; D011948:Receptors, Antigen, T-Cell