美国匹兹堡大学医学院Dario A. A. Vignali课题组发现，自身反应性CD8⁺T细胞受到由LAG3维持的耗竭样程序的抑制。2022年5月26日，《自然—免疫学》杂志在线发表了这项成果。

研究人员发现，胰岛内CD8⁺T细胞在表型、转录、表观遗传和代谢方面具有典型耗竭T细胞的特征，但仍保持重要的差异。这种"克制的"表型可以通过CD8⁺T细胞限制性地删除抑制性受体淋巴细胞激活基因3（LAG3）来扰乱和加速疾病。从机制上讲，LAG3缺陷的CD8⁺T细胞具有增强的效应子样功能，贩运到胰岛，并具有减弱的耗竭表型，这突出了耗竭程序在限制自身免疫中的生理作用，并将LAG3作为自身免疫治疗的靶标。

据悉，慢性病毒和肿瘤清除受损被归因于CD8⁺T细胞耗竭，这是一种分化状态，T细胞的效应功能减少和改变，在阻断抑制性受体后可部分逆转。耗竭程序和控制CD8⁺T细胞功能和命运的转录网络在自身免疫中的作用还不清楚。

附：英文原文

Title: Autoreactive CD8+ T cells are restrained by an exhaustion-like program that is maintained by LAG3

Author: Grebinoski, Stephanie, Zhang, Qianxia, Cillo, Anthony R., Manne, Sasikanth, Xiao, Hanxi, Brunazzi, Erin A., Tabib, Tracy, Cardello, Carly, Lian, Christine G., Murphy, George F., Lafyatis, Robert, Wherry, E. John, Das, Jishnu, Workman, Creg J., Vignali, Dario A. A.

Issue&Volume: 2022-05-26

Abstract: Impaired chronic viral and tumor clearance has been attributed to CD8+ T cell exhaustion, a differentiation state in which T cells have reduced and altered effector function that can be partially reversed upon blockade of inhibitory receptors. The role of the exhaustion program and transcriptional networks that control CD8+ T cell function and fate in autoimmunity is not clear. Here we show that intra-islet CD8+ T cells phenotypically, transcriptionally, epigenetically and metabolically possess features of canonically exhausted T cells, yet maintain important differences. This ‘restrained’ phenotype can be perturbed and disease accelerated by CD8+ T cell-restricted deletion of the inhibitory receptor lymphocyte activating gene 3 (LAG3). Mechanistically, LAG3-deficient CD8+ T cells have enhanced effector-like functions, trafficking to the islets, and have a diminished exhausted phenotype, highlighting a physiological role for an exhaustion program in limiting autoimmunity and implicating LAG3 as a target for autoimmune therapy.

DOI: 10.1038/s41590-022-01210-5

Source: https://www.nature.com/articles/s41590-022-01210-5