Anion exchanger 2 is critical for CD8+T cells to maintain pHi homeostasis and modulate immune responses
Anion exchanger 2 is critical for CD8+T cells to maintain pHi homeostasis and modulate immune responses
复制标题
DOI：
10.1002/eji.201344218
复制
发表时间：
2014-05-01
影响因子：
5.4
通讯作者：
Medina, Juan F.
中科院分区：
文献类型：
--
作者：
Concepcion, Axel R.;Salas, January T.;Medina, Juan F.
淋巴细胞的促有丝分裂刺激涉及细胞内pH（pH（i））的碱化。随后的pH（i）调节可能涉及通过Cl-/HCO 3-交换剂和/或具有酸负载能力的Na+-HCO 3-共转运体的HCO 3-挤出。这些机制的异常可能导致免疫功能障碍，正如缺乏Ae 2（一种广泛表达的酸装载剂，具有电中性和Na+非依赖性Cl-/HCO 3-阴离子交换活性）的小鼠中遇到的CD 8（+）T细胞扩增所表明的那样。在这里，我们报告了CD 8（+）T细胞，而不是CD 4（+）T细胞或其他淋巴细胞群体，是至关重要的依赖于Ae 2的pH（i）调节。虽然总淋巴细胞（包括分离的CD 4（+）T细胞）表现出Ae 1表达和Na+-HCO 3-共转运与酸化潜力，CD 8（+）T细胞缺乏这些酸负荷机制。在Ae 2-KO小鼠中，CD 4（+）而不是CD 8（+）T细胞上调这些潜在的Ae 2替代物。因此，Ae 2-KO CD 8（+）T细胞表现出碱化的pH（i），并在CD 3刺激后显著增加其pH（i）。此外，刺激的Ae 2缺陷型CD 8（+）T细胞显示出IL-2的细胞内产生和其受体IL-2 R的膜表达增强，以及细胞增殖和活化增加。这些发现表明，CD 8（+）T细胞严重依赖于Ae 2的pH（i）稳态和细胞增殖和活化的调节。因此，Ae 2构成了调节CD 8（+）T细胞应答的新靶点。
Mitogenic stimulation of lymphocytes involves alkalinization of intracellular pH (pH(i)). Subsequent pH(i) regulation may involve HCO3- extrusion through Cl-/HCO3- exchangers and/or Na+-HCO3- co-transporters with acid-loading capability. Abnormalities in these mechanisms could result in immune dysfunctions, as suggested by the CD8(+) T-cell expansion encountered in mice lacking Ae2 (a widely expressed acid loader with electroneutral and Na+-independent Cl-/HCO3- anion-exchange activity). Here we report that CD8(+) Tcells but not CD4(+) Tcells or other lymphocyte populations, are crucially dependent on Ae2 for pH(i) regulation. While total lymphocytes (including isolated CD4(+) Tcells) exhibit Ae1 expression and Na+-HCO3- co-transport with acidifying potential, CD8(+) Tcells lack these acid-loading mechanisms. In Ae2-KO mice, CD4(+) but not CD8(+) Tcells upregulate these potential Ae2 surrogates. As a consequence, Ae2-KO CD8(+) Tcells exhibit alkalinized pH(i), and dramatically increase their pH(i) upon CD3 stimulation. Moreover, stimulated Ae2-deficient CD8(+) Tcells show enhanced intracellular production of IL-2 and membrane expression of its receptor IL-2R, together with increased cell proliferation and activation. These findings demonstrate that CD8(+) Tcells are critically dependent on Ae2 for pH(i) homeostasis and tuning of cell proliferation and activation. Ae2 thus constitutes a novel target to modulate CD8(+) T-cell responses.