Ryanodine receptor signaling is required for anti-CD3-induced T cell proliferation, interleukin-2 synthesis, and interleukin-2 receptor signaling

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Abstract
Ryanodine receptors (RyR) are involved in regulating intracellular Ca++ mobilization in T lymphocytes. However, the importance of RyR signaling during T cell activation has not yet been determined. In this study, we have used the RyR‐selective antagonists, ruthenium red and dantrolene, to determine the effect of RyR blockade on T cell receptor‐mediated activation events and cytokine‐dependent T cell proliferation. Both ruthenium red and dantrolene inhibited DNA synthesis and cell division, as well as the synthesis of interleukin (IL)‐2 by T lymphocytes responding to mitogenic anti‐CD3 antibody. Blockade of RyR at initiation of culture or as late as 24 h after T cell receptor stimulation inhibited T cell proliferation, suggesting a requirement for sustained RyR signaling during cell cycle progression. Although flow cytometry revealed that RyR blockade had little effect on activation‐induced expression of the α chain (CD25) of the high affinity IL‐2 receptor, the inhibitory effect of RyR antagonists could not be reversed by the addition of exogenous IL‐2 at initiation of culture. In addition, both ruthenium red and dantrolene had a strong inhibitory effect on IL‐2‐dependent proliferation of CTLL‐2 T cells. These data indicate that RyR are involved in regulating IL‐2 receptor signaling that drives T cell progression through the cell cycle. We conclude that RyR‐associated Ca++ signaling regulates T cell proliferation by promoting both IL‐2 synthesis and IL‐2‐dependent cell cycle progression.