Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control.
Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control.
复制标题
DOI：
10.1172/jci157549
复制
发表时间：
2022-06-01
影响因子：
15.9
通讯作者：
Saez-Cirion, Asier
中科院分区：
文献类型：
--
作者：
Perdomo-Celis, Federico;Passaes, Caroline;Monceaux, Valerie;Volant, Stevenn;Boufassa, Faroudy;de Truchis, Pierre;Marcou, Morgane;Bourdic, Katia;Weiss, Laurence;Jung, Corinne;Bourgeois, Christine;Goujard, Cecile;Meyer, Laurence;Muller-Trutwin, Michaela;Lambotte, Olivier;Saez-Cirion, Asier
病毒特异性CD 8 + T细胞在HIV-1天然控制者中发挥核心作用，以在缺乏抗逆转录病毒治疗的情况下维持受抑制的病毒血症。这些细胞显示出记忆程序，赋予它们干性特性、高存活率、多功能性、增殖能力、代谢可塑性和抗病毒潜力。记忆性CD 8 + T细胞的这种特性的发展和维持似乎对实现自然的HIV-1控制至关重要。在这里，我们表明，针对信号通路Wnt/转录因子T细胞因子1（Wnt/TCF-1）和mTORC通过GSK 3抑制重编程HIV特异性CD 8 + T细胞从noncontrollers促进与感染的自然控制相关的功能能力。这些重编程细胞的特征包括富集TCF-1+低分化亚群、对抗原的上级应答、存活率提高、多功能性、代谢可塑性、mTORC 1依赖性降低、对γ-链细胞因子的应答改善以及更强的HIV抑制能力。因此，这种CD 8 + T细胞重编程与其他可用的免疫调节剂相结合，可能代表了在寻求HIV-1治愈中的过继细胞治疗的有希望的策略。
Virus-specific CD8+ T cells play a central role in HIV-1 natural controllers to maintain suppressed viremia in the absence of antiretroviral therapy. These cells display a memory program that confers them stemness properties, high survival, polyfunctionality, proliferative capacity, metabolic plasticity, and antiviral potential. The development and maintenance of such qualities by memory CD8+ T cells appear crucial to achieving natural HIV-1 control. Here, we show that targeting the signaling pathways Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) and mTORC through GSK3 inhibition to reprogram HIV-specific CD8+ T cells from noncontrollers promoted functional capacities associated with natural control of infection. Features of such reprogrammed cells included enrichment in TCF-1+ less-differentiated subsets, a superior response to antigen, enhanced survival, polyfunctionality, metabolic plasticity, less mTORC1 dependency, an improved response to γ-chain cytokines, and a stronger HIV-suppressive capacity. Thus, such CD8+ T cell reprogramming, combined with other available immunomodulators, might represent a promising strategy for adoptive cell therapy in the search for an HIV-1 cure.