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MYB协调T细胞的耗竭和对检查点抑制的反应
2022-08-21 22:45

澳大利亚墨尔本大学Axel Kallies、德国慕尼黑工业大学Veit R. Buchholz等研究人员合作发现,MYB协调T细胞的耗竭和对检查点抑制的反应,该项研究成果于2022年8月17日在线发表在《自然》杂志上。

研究人员表示,对慢性病毒感染或癌症响应的CD8+T细胞的特点是表达抑制性受体,如程序性细胞死亡蛋白1(PD-1),以及细胞因子的生产受损。这种功能受限的状态(被称为T细胞耗竭)由表达转录因子T细胞因子1(TCF1)的耗竭T(TPEX)细胞前体维持,这些细胞自我更新并产生TCF1-耗竭效应T细胞。

研究人员,在慢性感染期间,耗竭T细胞的长期增殖潜力、多能性和再增殖能力选择性地保留在一小部分转录不同的CD62L+TPEX细胞中。转录因子MYB不仅对CD62L+TPEX细胞的发育和抗病毒CD8+T细胞反应的维持至关重要,而且还能诱导功能耗竭,从而防止致命的免疫病理。此外,对PD-1检查点抑制反应的增殖爆发完全来源于CD62L+TPEX细胞,并依赖于MYB。这些研究结果表明,CD62L+TPEX细胞是一个干细胞群,并且是维持长期抗病毒免疫力和对免疫疗法反应性的核心。此外,结果表明MYB是耗竭T细胞反应两个基本方面的转录协调者:效应功能的下调和自我更新能力的长期保存。

附:英文原文

Title: MYB orchestrates T cell exhaustion and response to checkpoint inhibition

Author: Tsui, Carlson, Kretschmer, Lorenz, Rapelius, Svenja, Gabriel, Sarah S., Chisanga, David, Knpper, Konrad, Utzschneider, Daniel T., Nssing, Simone, Liao, Yang, Mason, Teisha, Torres, Santiago Valle, Wilcox, Stephen A., Kanev, Krystian, Jarosch, Sebastian, Leube, Justin, Nutt, Stephen L., Zehn, Dietmar, Parish, Ian A., Kastenmller, Wolfgang, Shi, Wei, Buchholz, Veit R., Kallies, Axel

Issue&Volume: 2022-08-17

Abstract: CD8+ T cells that respond to chronic viral infections or cancer are characterized by the expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and by the impaired production of cytokines. This state of restrained functionality—which is referred to as T cell exhaustion1,2—is maintained by precursors of exhausted T (TPEX) cells that express the transcription factor T cell factor 1 (TCF1), self-renew and give rise to TCF1 exhausted effector T cells3,4,5,6. Here we show that the long-term proliferative potential, multipotency and repopulation capacity of exhausted T cells during chronic infection are selectively preserved in a small population of transcriptionally distinct CD62L+ TPEX cells. The transcription factor MYB is not only essential for the development of CD62L+ TPEX cells and maintenance of the antiviral CD8+ T cell response, but also induces functional exhaustion and thereby prevents lethal immunopathology. Furthermore, the proliferative burst in response to PD-1 checkpoint inhibition originates exclusively from CD62L+ TPEX cells and depends on MYB. Our findings identify CD62L+ TPEX cells as a stem-like population that is central to the maintenance of long-term antiviral immunity and responsiveness to immunotherapy. Moreover, they show that MYB is a transcriptional orchestrator of two fundamental aspects of exhausted T cell responses: the downregulation of effector function and the long-term preservation of self-renewal capacity.

DOI: 10.1038/s41586-022-05105-1

Source: https://www.nature.com/articles/s41586-022-05105-1

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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