Arf1 and Arf6 Synergistically Maintain Survival of T Cells during Activation
Arf1 and Arf6 Synergistically Maintain Survival of T Cells during Activation
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DOI：
10.4049/jimmunol.2000971
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发表时间：
2021-01-15
影响因子：
4.4
通讯作者：
Matsuda, Satoshi
中科院分区：
文献类型：
--
作者：
Sumiyoshi, Mami;Kotani, Yui;Matsuda, Satoshi
ADP-核糖基化因子（Arf）家族属于Ras超家族，由六个成员Arf 1-Arf 6组成，在鸟嘌呤核苷酸交换因子（GEFs）和GTP酶激活蛋白的调控下协调囊泡的运输。已经确定，布雷菲德菌素A（ArfGEF的有效抑制剂）阻断活化T细胞的细胞因子分泌，表明Arf途径在T细胞功能中起重要作用。在本研究中，由于Arf 1和Arf 6是Arf家族中最具特征的成员，我们建立了T谱系特异性Arf 1缺陷、Arf 6缺陷和Arf 1/6双缺陷小鼠，以了解Arf通路在免疫系统中的生理作用。与我们的预期相反，Arf缺乏对活化T细胞的细胞因子分泌几乎没有影响。相反，缺乏Arf 1和Arf 6，但Arf 1和Arf 6都不单独缺乏，使得幼稚T细胞在TCR刺激后容易凋亡，因为Bcl-2家族成员的表达不平衡。我们进一步证明，Arf 1/6缺陷的T细胞会导致自身免疫性疾病，如结肠炎和实验性自身免疫性脑脊髓炎，而抗体反应在Th 2极化条件下似乎是正常的。我们的研究结果揭示了一个意想不到的作用，在TCR诱导的活化过程中的T细胞的生存Arf通路及其作为治疗靶点在自身免疫性疾病的潜力。
ADP-ribosylation factor (Arf) family consisting of six family members, Arf1-Arf6, belongs to Ras superfamily and orchestrates vesicle trafficking under the control of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins. It is well established that brefeldin A, a potent inhibitor of ArfGEFs, blocks cytokine secretion from activated T cells, suggesting that the Arf pathway plays important roles in T cell functions. In this study, because Arf1 and Arf6 are the best-characterized members among Arf family, we established T lineage-specific Arf1-deficient, Arf6-deficient, and Arf1/6 double-deficient mice to understand physiological roles of the Arf pathway in the immune system. Contrary to our expectation, Arf deficiency had little or no impact on cytokine secretion from the activated T cells. In contrast, the lack of both Arf1 and Arf6, but neither Arf1 nor Arf6 deficiency alone, rendered naive T cells susceptible to apoptosis upon TCR stimulation because of imbalanced expression of Bcl-2 family members. We further demonstrate that Arf1/6 deficiency in T cells alleviates autoimmune diseases like colitis and experimental autoimmune encephalomyelitis, whereas Ab response under Th2-polarizing conditions is seemingly normal. Our findings reveal an unexpected role for the Arf pathway in the survival of T cells during TCR-induced activation and its potential as a therapeutic target in the autoimmune diseases.