Department of Medicine, UCSF, San Francisco, California, USA.
Institute of Human Genetics, University of the Philippines-National Institutes of Health, Manila, Philippines.
JCI Insight. 2021 Feb 8;6(3):136648. doi: 10.1172/jci.insight.136648.
Although many HIV cure strategies seek to expand HIV-specific CD8+ T cells to control the virus, all are likely to fail if cellular exhaustion is not prevented. A loss in stem-like memory properties (i.e., the ability to proliferate and generate secondary effector cells) is a key feature of exhaustion; little is known, however, about how these properties are regulated in human virus-specific CD8+ T cells. We found that virus-specific CD8+ T cells from humans and nonhuman primates naturally controlling HIV/SIV infection express more of the transcription factor TCF-1 than noncontrollers. HIV-specific CD8+ T cell TCF-1 expression correlated with memory marker expression and expansion capacity and declined with antigenic stimulation. CRISPR-Cas9 editing of TCF-1 in human primary T cells demonstrated a direct role in regulating expansion capacity. Collectively, these data suggest that TCF-1 contributes to the regulation of the stem-like memory property of secondary expansion capacity of HIV-specific CD8+ T cells, and they provide a rationale for exploring the enhancement of this pathway in T cell-based therapeutic strategies for HIV.
虽然许多 HIV 治愈策略都试图扩增 HIV 特异性 CD8+ T 细胞以控制病毒，但如果不防止细胞耗竭，所有策略都可能失败。丧失干细胞样记忆特性（即增殖和产生次级效应细胞的能力）是耗竭的一个关键特征；然而，人们对这些特性如何在人类病毒特异性 CD8+ T 细胞中受到调节知之甚少。我们发现，自然控制 HIV/SIV 感染的人类和非人类灵长类动物的病毒特异性 CD8+ T 细胞表达的转录因子 TCF-1 多于非控制器。HIV 特异性 CD8+ T 细胞 TCF-1 的表达与记忆标志物的表达和扩增能力相关，并随着抗原刺激而下降。CRISPR-Cas9 编辑人类原代 T 细胞中的 TCF-1 表明其在调节扩增能力方面具有直接作用。综上所述，这些数据表明 TCF-1 有助于调节 HIV 特异性 CD8+ T 细胞的次级扩增能力的干细胞样记忆特性，并为探索在基于 T 细胞的 HIV 治疗策略中增强该途径提供了依据。
