TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection
TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection
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DOI：
10.1038/s41586-019-1326-9
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发表时间：
2019-07-11
期刊：
影响因子：
64.8
通讯作者：
Zehn, Dietmar
中科院分区：
文献类型：
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作者：
Alfei, Francesca;Kanev, Kristiyan;Zehn, Dietmar
细胞毒性 T 细胞是针对病毒感染和恶性肿瘤的保护性免疫的重要介质，也是免疫治疗方法的关键目标。然而，长时间暴露于同源抗原通常会减弱 T 细胞的效应能力并限制其治疗潜力 (1-4)。这一过程称为 T 细胞耗竭或功能障碍(1)，表现为表观遗传强制的基因调控变化，减少细胞因子和效应分子的表达并上调抑制性受体的表达，例如程序性细胞死亡 1 (PD-1)(5-8)。诱导和稳定耗竭 T 细胞的表型和功能特征的潜在分子机制仍知之甚少(9-12)。在此，我们报告小鼠耗竭 T 细胞群的发育和维持需要胸腺细胞选择相关的高迁移率族盒 (TOX) 蛋白 (13-15)。 TOX 是由 T 细胞受体的高抗原刺激诱导的，与小鼠淋巴细胞性脉络丛脑膜炎病毒和人类丙型肝炎病毒慢性感染期间出现的疲惫表型相关。去除其 DNA 结合域会降低 PD-1 在 mRNA 和蛋白质水平上的表达，增加细胞因子的产生，并导致更具多功能性的 T 细胞表型。具有这种缺失的T细胞最初介导效应功能增强并引起更严重的免疫病理学，但最终其数量大幅下降，特别是在TCF-1(+)自我更新T细胞亚群中。总而言之，我们表明 TOX 是 T 细胞功能障碍正常进展和慢性感染期间 T 细胞耗竭维持的关键因素，并提供了 CD8 T 细胞固有效应功能的抑制和免疫病理保护之间的联系。
Cytotoxic T cells are essential mediators of protective immunity to viral infection and malignant tumours and are a key target of immunotherapy approaches. However, prolonged exposure to cognate antigens often attenuates the effector capacity of T cells and limits their therapeutic potential(1-4). This process, known as T cell exhaustion or dysfunction(1), is manifested by epigenetically enforced changes in gene regulation that reduce the expression of cytokines and effector molecules and upregulate the expression of inhibitory receptors such as programmed cell-death 1 (PD-1)(5-8). The underlying molecular mechanisms that induce and stabilize the phenotypic and functional features of exhausted T cells remain poorly understood(9-12). Here we report that the development and maintenance of populations of exhausted T cells in mice requires the thymocyte selection-associated high mobility group box (TOX) protein(13-15). TOX is induced by high antigen stimulation of the T cell receptor and correlates with the presence of an exhausted phenotype during chronic infections with lymphocytic choriomeningitis virus in mice and hepatitis C virus in humans. Removal of its DNA-binding domain reduces the expression of PD-1 at the mRNA and protein level, augments the production of cytokines and results in a more polyfunctional T cell phenotype. T cells with this deletion initially mediate increased effector function and cause more severe immunopathology, but ultimately undergo a massive decline in their quantity, notably among the subset of TCF-1(+) self-renewing T cells. Altogether, we show that TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infection, and provide a link between the suppression of effector function intrinsic to CD8 T cells and protection against immunopathology.