Ryanodine receptor signaling is required for anti-CD3-induced T cell proliferation, interleukin-2 synthesis, and interleukin-2 receptor signaling
Ryanodine receptor signaling is required for anti-CD3-induced T cell proliferation, interleukin-2 synthesis, and interleukin-2 receptor signaling
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DOI：
10.1002/jcb.20064
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发表时间：
2004-05-15
影响因子：
4
通讯作者：
Hoskin, DW
中科院分区：
文献类型：
--
作者：
Conrad, DM;Hanniman, EA;Hoskin, DW
Ryanodine受体(RyR)参与调节T淋巴细胞内钙离子的动员。然而，RyR信号在T细胞激活过程中的重要性尚未确定。在这项研究中，我们使用了RyR选择性拮抗剂Ru红和丹曲林，以确定RyR阻断对T细胞受体介导的激活事件和细胞因子依赖的T细胞增殖的影响。Ru红和丹曲林均能抑制CD3抗体诱导的T淋巴细胞DNA合成和细胞分裂，以及IL-2的合成。在培养开始时或在T细胞受体刺激后24小时阻断RyR可抑制T细胞的增殖，提示在细胞周期进程中需要持续的RyR信号。虽然流式细胞术显示RyR阻断剂对激活诱导的高亲和力IL-2受体α链(CD25)的表达影响不大，但在培养开始时加入外源性IL-2不能逆转RyR拮抗剂的抑制作用。此外，Ru红和丹曲烯对依赖IL-2的CTLL-2T细胞的增殖均有较强的抑制作用。这些数据表明，RyR参与调节IL-2受体信号，该信号驱动T细胞在细胞周期中前进。我们得出结论，RyR相关的Ca++信号通过促进IL-2的合成和IL-2依赖的细胞周期进程来调节T细胞的增殖。(C)2004年Wiley-Liss公司
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 alpha 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. (C) 2004 Wiley-Liss, Inc.