A multiple-oscillator mechanism underlies antigen-induced Ca oscillations in Jurkat T-cells.

T-cell receptor stimulation triggers cytosolic Ca signaling by inositol-1,4,5-trisphosphate (IP)-mediated Ca release from the endoplasmic reticulum (ER) and Ca entry through Ca release-activated Ca (CRAC) channels gated by ER-located stromal-interacting molecules (STIM1/2). Physiologically, cytosolic Ca signaling manifests as regenerative Ca oscillations, which are critical for nuclear factor of activated T-cells-mediated transcription. In most cells, Ca oscillations are thought to originate from IP receptor-mediated Ca release, with CRAC channels indirectly sustaining them through ER refilling. Here, experimental and computational evidence support a multiple-oscillator mechanism in Jurkat T-cells whereby both IP receptor and CRAC channel activities oscillate and directly fuel antigen-evoked Ca oscillations, with the CRAC channel being the major contributor. KO of either STIM1 or STIM2 significantly reduces CRAC channel activity. As such, STIM1 and STIM2 synergize for optimal Ca oscillations and activation of nuclear factor of activated T-cells 1 and are essential for ER refilling. The loss of both STIM proteins abrogates CRAC channel activity, drastically reduces ER Ca content, severely hampers cell proliferation and enhances cell death. These results clarify the mechanism and the contribution of STIM proteins to Ca oscillations in T-cells.