Meuth Sven G, Bittner Stefan, Meuth Patrick, Simon Ole J, Budde Thomas, Wiendl Heinz
Department of Neurology, University of Wuerzburg, Wuerzburg, Germany.
J Biol Chem. 2008 May 23;283(21):14559-70. doi: 10.1074/jbc.M800637200. Epub 2008 Mar 28.
Two major K(+) channels are expressed in T cells, (i) the voltage-dependent K(V)1.3 channel and (ii) the Ca(2+)-activated K(+) channel KCa 3.1 (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 ( approximately 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. Pretreatment 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 K(2)P 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.
两种主要的钾离子通道在T细胞中表达，（i）电压依赖性钾离子通道K(V)1.3和（ii）钙激活钾离子通道KCa 3.1（IKCa通道）。二者在体外和体内动物模型中均对T细胞效应功能产生关键影响。在此，我们鉴定并表征了TWIK相关酸敏感钾离子通道1（TASK1）和TASK3，它们是T淋巴细胞上重要的第三种钾离子电导。T淋巴细胞组成性表达TASK1和-3蛋白。应用半选择性TASK阻滞剂可显著降低细胞因子产生和细胞增殖。对CD3(+) T细胞上的TASK通道进行干扰，膜片钳记录显示出外向电流呈剂量依赖性降低（约40%），提示存在TASK通道，这一发现通过计算模型得到证实。我们在多发性硬化症的实验模型——过继转移实验性自身免疫性脑脊髓炎中探讨了这些发现的体内相关性。用TASK调节剂对髓鞘碱性蛋白特异性致脑炎T淋巴细胞进行预处理，与Lewis大鼠疾病进程的显著改善相关。这些数据表明K(2)P通道是T淋巴细胞上新的钾离子电导，对T细胞效应功能有关键影响，并确定了T细胞介导的自身免疫性疾病免疫调节的一个可能分子靶点。
