PNAS：免疫检查点蛋白VISTA和PD-1非重复性调控了鼠类T细胞反应

摘要 : 来自威斯康星医学院、中国药科大学、Norris Cotton癌症中心等机构的研究人员证实，免疫检查点蛋白VISTA和PD-1非重复性调控了鼠类T细胞反应。这一重要的研究发现发布在5月11日的《美国国家科学院院刊》（PNAS）杂志上。

免疫检查点控制共刺激和共抑制信号的平衡，而共刺激和共抑制信号在维持自身耐受和调节T细胞应答的幅值与持续时间方面具有重要作用。以往的研究证实，程序性细胞死亡的蛋白1(PD-1)、LAG3和TIM3等多种免疫检查点蛋白共同表达于免疫细胞之上，彼此协同发挥功能。

VISTA是近期发现的一个免疫检查点蛋白，研究发现它可以抑制t细胞的反应。但目前尚不清楚VISTA是否与诸如PD-1一类的其他的免疫检查点蛋白协同发挥作用。

在这篇文章中研究人员报告称，他们鉴别了VISTA基因敲除(KO)小鼠、PD-1 KO小鼠和VISTA/PD-1双KO小鼠的免疫反应特征。他们在两个单基因敲除小鼠中均观察到了慢性炎症和T细胞自发性激活，证实了它们之间功能的非重复性。而VISTA/PD-1双基因敲除小鼠比单基因敲除小鼠显示出显著高水平的这些表型。

当研究人员让这些小鼠与易于形成中枢系统炎症性自身免疫病的2D2 T细胞受体转基因小鼠交配时，发现相比于单基因敲除小鼠，双基因敲除小鼠的疾病外显率水平显著增高。与之相一致，在VISTA/PD-1双基因敲除小鼠中，T细胞对于外源抗原的反应程度以协同性方式增高。组合特异性针对VISTA和PD-L1的单克隆抗体可以获得最佳的清除肿瘤治疗效应。

新研究证实了VISTA在控制T细胞激活过程中发挥了不同于PD-1/PD-L1信号通路的非重复作用。这些研究结果为共同靶向VISTA和PD-1信号通路来治疗诸如癌症一类的T细胞调控性疾病提供了理论依据。

原文标题：Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-Cell responses

原文摘要：V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a negative immune-checkpoint protein that suppresses T-cell responses. To determine whether VISTA synergizes with another immune-checkpoint, programmed death 1 (PD-1), this study characterizes the immune responses in VISTA-deficient, PD-1-deficient (KO) mice and VISTA/PD-1 double KO mice. Chronic inflammation and spontaneous activation of T cells were observed in both single KO mice, demonstrating their nonredundancy. However, the VISTA/PD-1 double KO mice exhibited significantly higher levels of these phenotypes than the single KO mice. When bred onto the 2D2 T-cell receptor transgenic mice, which are predisposed to development of inflammatory autoimmune disease in the CNS, the level of disease penetrance was significantly enhanced in the double KO mice compared with in the single KO mice. Consistently, the magnitude of T-cell response toward foreign antigens was synergistically higher in the VISTA/PD-1 double KO mice. A combinatorial blockade using monoclonal antibodies specific for VISTA and PD-L1 achieved optimal tumor-clearing therapeutic efficacy. In conclusion, our study demonstrates the nonredundant role of VISTA that is distinct from the PD-1/PD-L1 pathway in controlling T-cell activation. These findings provide the rationale to concurrently target VISTA and PD-1 pathways for treating T-cell-regulated diseases such as cancer.

作者：秩名

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