Store-operated Ca2+ influx causes Ca2+ release from the intracellular Ca2+ channels that is required for T cell activation

The precise control of many T cell functions relies on cytosolic Ca2(+) dynamics that is shaped by the Ca2(+) release from the intracellular store and extracellular Ca2(+) influx. The Ca2(+) influx activated following T cell receptor (TCR)-mediated store depletion is considered to be a major mechanism for sustained elevation in cytosolic Ca2(+) concentration ([ Ca2(+)](i)) necessary for T cell activation, whereas the role of intracellular Ca2(+) release channels is believed to be minor. We found, however, that in Jurkat T cells [Ca2(+)] i elevation observed upon activation of the store-operated Ca2(+) entry (SOCE) by passive store depletion with cyclopiazonic acid, a reversible blocker of sarco-endoplasmic reticulum Ca2(+)-ATPase, inversely correlated with store refilling. This indicated that intracellular Ca2(+) release channels were activated in parallel with SOCE and contributed to global [ Ca2(+)] i elevation. Pretreating cells with (-)- xestospongin C (10 mu M) or ryanodine (400 mu M), the antagonists of inositol 1,4,5-trisphosphate receptor (IP3R) or ryanodine receptor (RyR), respectively, facilitated store refilling and significantly reduced [Ca2(+)] i elevation evoked by the passive store depletion or TCR ligation. Although the Ca2(+) release from the IP3R can be activated by TCR stimulation, the Ca2(+) release from the RyR was not inducible via TCR engagement and was exclusively activated by the SOCE. We also established that inhibition of IP3R or RyR down-regulated T cell proliferation and T-cell growth factor interleukin 2 production. These studies revealed a new aspect of [Ca2(+)]i signaling in T cells, that is SOCE-dependent Ca2(+) release via IP3R and/or RyR, and identified the IP3R and RyR as potential targets for manipulation of Ca2+-dependent functions of T lymphocytes.