TWIK-related acid-sensitive K+ channel 1 (TASK1) and TASK3 critically influence T lymphocyte effector functions
TWIK-related acid-sensitive K+ channel 1 (TASK1) and TASK3 critically influence T lymphocyte effector functions
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DOI：
10.1074/jbc.m800637200
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发表时间：
2008-05-23
影响因子：
4.8
通讯作者：
Wiendl, Heinz
中科院分区：
文献类型：
--
作者：
Meuth, Sven G.;Bittner, Stefan;Wiendl, Heinz
两种主要的K+通道在T细胞中表达，(i)电压依赖性K(V)1.3通道和（ii） Ca2+激活的K+通道KCa3.1 （IKCa通道）。两者在体外和体内动物模型中都严重影响T细胞效应功能。在这里，我们发现并表征了twik相关的酸敏感钾通道1 （TASK1）和TASK3是T淋巴细胞上重要的第三个K+传导。T淋巴细胞组成性表达TASK1和-3蛋白。半选择性任务阻断剂的应用导致细胞因子产生和细胞增殖的显著减少。对CD3(+) T细胞上TASK通道的干扰显示，膜片钳记录显示TASK通道的外向电流的剂量依赖性减少（类似于40%），这一发现被计算模型证实。我们的研究结果的体内相关性在多发性硬化症，过继性转移实验性自身免疫性脑脊髓炎的实验模型中得到了解决。用TASK调节剂预处理髓鞘碱性蛋白特异性脑源性T淋巴细胞与Lewis大鼠病程的显著改善相关。这些数据介绍了K2P通道作为T淋巴细胞上的新型钾传导通道，对T细胞效应功能有重要影响，并确定了T细胞介导的自身免疫性疾病中免疫调节的可能分子靶点。
Two major K+ channels are expressed in T cells,(i) the voltage dependent K(V)1.3 channel and (ii) the Ca2+-activated K+ channel KCa3.1 (IKCa channel). Both critically influence T cell effector functions in vitro and animal models in vivo. Here we identify and characterize TWIK-related acid- sensitive potassium channel 1 (TASK1) and TASK3 as an important third K+ conductance on T lymphocytes. T lymphocytes constitutively express TASK1 and -3 protein. Application of semi-selective TASK blockers resulted in a significant reduction of cytokine production and cell proliferation. Interference with TASK channels on CD3(+) T cells revealed a dose- dependent reduction (similar to 40%) of an outward current in patch clamp recordings indicative of TASK channels, a finding confirmed by computational modeling. In vivo relevance of our findings was addressed in an experimental model of multiple sclerosis, adoptive transfer experimental autoimmune encephalomyelitis. Pre-treatment of myelin basic protein-specific encephalitogenic T lymphocytes with TASK modulators was associated with significant amelioration of the disease course in Lewis rats. These data introduce K2P channels as novel potassium conductance on T lymphocytes critically influencing T cell effector function and identify a possible molecular target for immunomodulation in T cell-mediated autoimmune disorders.