Arginine deficiency leads to impaired cofilin dephosphorylation in activated human T lymphocytes
Arginine deficiency leads to impaired cofilin dephosphorylation in activated human T lymphocytes
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DOI：
10.1093/intimm/dxs004
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发表时间：
2012-05-01
影响因子：
4.4
通讯作者：
Munder, Markus
中科院分区：
文献类型：
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作者：
Feldmeyer, Nadja;Wabnitz, Guido;Munder, Markus
氨基酸精氨酸在感染、炎性疾病和肿瘤生长期间基本上参与免疫应答的调节。精氨酸缺乏（例如，由于骨髓细胞酶精氨酸酶）抑制活化T淋巴细胞的增殖和效应器功能。在这里，我们研究了介导这种抑制人类T淋巴细胞的细胞内机制。我们的蛋白质组学分析显示，在没有精氨酸的情况下，肌动蛋白结合蛋白cofilin在T细胞活化后去磷酸化受损。我们发现，这与肌动蛋白聚合的改变和受损的积累CD 2和CD 3在T细胞抗原呈递细胞缀合物的免疫突触的发展。相反，在没有精氨酸的情况下，人T淋巴细胞中的T细胞细胞因子合成受到差异调节。虽然某些细胞因子（例如IFN-γ）的产生严重减少，但T淋巴细胞产生不依赖于细胞外精氨酸的其他细胞因子（例如IL-2）。MEK和PI 3 K活性与受损的cofilin去磷酸化相关地受到调节。最后，我们表明，由于精氨酸酶介导的精氨酸耗尽，在粒细胞主导的脓性微环境中激活的人类T细胞中也可以检测到丝切蛋白脱磷酸化受损。我们的新结果确定cofilin作为一个潜在的调节人T细胞活化条件下的炎症精氨酸缺乏症。
The amino acid arginine is fundamentally involved in the regulation of the immune response during infection, inflammatory diseases and tumor growth. Arginine deficiency (e.g. due to the myeloid cell enzyme arginase) inhibits proliferation and effector functions of activated T lymphocytes. Here, we studied intracellular mechanisms mediating this suppression of human T lymphocytes. Our proteomic analysis revealed an impaired dephosphorylation of the actin-binding protein cofilin upon T-cell activation in the absence of arginine. We show that this correlates with alteration of actin polymerization and impaired accumulation of CD2 and CD3 in the evolving immunological synapse in T cell-antigen presenting cells conjugates. In contrast, T-cell cytokine synthesis is differentially regulated in human T lymphocytes in the absence of arginine. While the production of certain cytokines (e.g. IFN-gamma) is severely reduced, T lymphocytes produce other cytokines (e.g. IL-2) independent of extracellular arginine. MEK and PI3K activity are reciprocally regulated in association with impaired cofilin dephosphorylation. Finally, we show that impaired cofilin dephosphorylation is also detectable in human T cells activated in a granulocyte-dominated purulent micromilieu due to arginase-mediated arginine depletion. Our novel results identify cofilin as a potential regulator of human T-cell activation under conditions of inflammatory arginine deficiency.