美国国立卫生研究院Tuoqi Wu课题组在研究中取得进展。他们的研究通过单细胞RNA测序揭示在慢性感染中，TOX是调控慢性感染过程中CD8⁺T细胞的长期存活的关键因子。 这一研究成果于2019年7月发表在国际顶尖学术期刊《自然—免疫学》上。

通过比较急性和慢性病毒感染的CD8⁺T细胞的单细胞转录组和表观遗传谱，该课题组人员发现祖细胞样CD8⁺T细胞在T细胞应答峰值之前变得与记忆前体细胞不同。小组发现了含有Tox的共表达基因模块，其在祖细胞样细胞中表现出比记忆前体细胞更高的转录活性，与更丰富的活性组蛋白标记相关。此外，胸腺细胞选择与高迁移率族蛋白盒TOX相关，促进了抗病毒CD8⁺T细胞的持久性，并且是祖细胞样CD8⁺T细胞编程所必需的。因此，长期的CD8⁺T细胞免疫慢性病毒感染需要独特的转录和表观遗传程序，与转录因子TOX相关。

据介绍，祖细胞样CD8⁺T细胞介导对慢性感染和癌症的长期免疫，并对免疫检查点阻断作出有效反应。这些细胞与记忆前体细胞共享转录调节因子，包括T细胞特异性转录因子1（TCF1），但尚不清楚它们是否采用不同的程序来适应免疫抑制环境。

附：英文原文

Title: Single-cell RNA-seq reveals TOX as a key regulator of CD8 + T cell persistence in chronic infection

Author: Chen Yao, Hong-Wei Sun, Neal E. Lacey, Yun Ji, E. Ashley Moseman, Han-Yu Shih, Elisabeth F. Heuston, Martha Kirby, Stacie Anderson, Jun Cheng, Omar Khan, Robin Handon, Julie Reilley, Jessica Fioravanti, Jinhui Hu, Selamawit Gossa, E. John Wherry, Luca Gattinoni, Dorian B. McGavern, John J. OShea, Pamela L. Schwartzberg, Tuoqi Wu

Issue&Volume: Volume 20 Issue 7, July 2019

Abstract: Progenitor-like CD8+ T cells mediate long-term immunity to chronic infection and cancer and respond potently to immune checkpoint blockade. These cells share transcriptional regulators with memory precursor cells, including T cell-specific transcription factor 1 (TCF1), but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. By comparing the single-cell transcriptomes and epigenetic profiles of CD8+ T cells responding to acute and chronic viral infections, we found that progenitor-like CD8+ T cells became distinct from memory precursor cells before the peak of the T cell response. We discovered a coexpression gene module containing Tox that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursor cells. Moreover, thymocyte selection-associated high mobility group box protein TOX (TOX) promoted the persistence of antiviral CD8+ T cells and was required for the programming of progenitor-like CD8+ T cells. Thus, long-term CD8+ T cell immunity to chronic viral infection requires unique transcriptional and epigenetic programs associated with the transcription factor TOX.

DOI: 10.1038/s41590-019-0403-4

Source:https://www.nature.com/articles/s41590-019-0403-4