A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression
A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression
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DOI：
10.1038/nm1721
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发表时间：
2008-03-01
期刊：
影响因子：
82.9
通讯作者：
Chen, Si-Yi
中科院分区：
文献类型：
--
作者：
Song, Xiao-Tong;Evel-Kabler, Kevin;Chen, Si-Yi
调节性T细胞(T-reg细胞)抑制自身反应性免疫反应，限制肿瘤疫苗的疗效；然而，选择性地消除或抑制T-reg细胞仍然是一个挑战。本研究发现，Toll样受体和肿瘤坏死因子受体信号通路的负调控因子锌指A20在控制树突状细胞(DC)的成熟、细胞因子的产生和免疫刺激活性方面起着关键作用。A20沉默的DC表现出自发和增强的共刺激分子和促炎细胞因子的表达，并对T细胞亚群有不同的影响：它们抑制T-reg细胞和过度激活的肿瘤浸润性细胞毒性T细胞和T辅助细胞，后者产生白细胞介素6和肿瘤坏死因子-α，并且对T-reg细胞介导的抑制无效。因此，本研究确定A20是一种抗原递呈衰减剂，在启动和效应阶段都控制抗肿瘤免疫反应，并提供了一种策略，以抗原特异性的方式克服T-reg细胞介导的抑制，减少直接针对T-reg细胞的需要。
Regulatory T cells (T-reg cells) suppress autoreactive immune responses and limit the efficacy of tumor vaccines; however, it remains a challenge to selectively eliminate or inhibit T-reg cells. In this study, the zinc-finger A20, a negative regulator of the Toll-like receptor and tumor necrosis factor receptor signaling pathways, was found to play a crucial part in controlling the maturation, cytokine production and immunostimulatory potency of dendritic cells (DCs). A20-silenced DCs showed spontaneous and enhanced expression of costimulatory molecules and proinflammatory cytokines and had different effects on T cell subsets: they inhibited T-reg cells and hyperactivated tumor-infiltrating cytotoxic T lymphocytes and T helper cells that produced interleukin-6 and tumor necrosis factor-alpha and were refractory to T-reg cell-mediated suppression. Hence, this study identifies A20 as an antigen presentation attenuator in control of antitumor immune responses during both the priming and the effector phases and provides a strategy to overcome T-reg cell-mediated suppression in an antigen-specific manner, reducing the need to directly target T-reg cells.