美国宾夕法尼亚大学E. John Wherry小组发现，Stat5对抗转录因子Tox并在慢性抗原暴露期间将衰竭的CD8⁺ T细胞重新组装为持久的效应样状态。相关论文发表在2023年12月12日出版的《免疫》杂志上。

研究人员表示，将衰竭的CD8⁺ T（Tex）细胞重新连接到功能状态仍然是一项治疗挑战。Tex细胞由转录因子Tox进行表观遗传编程。然而，当Tex细胞从祖细胞（Tex^prog）过渡到中间亚群（Tex^int）和末端亚群（Tex^term）时，会发生表观遗传重塑，这表明了发育的灵活性。

研究人员报道了Tex细胞亚群之间的表观遗传转变，发现Stat5a和Tox之间存在相互拮抗的回路。Stat5指导了Tex^int细胞的形成，并在Tex^prog细胞到Tex^int细胞的转变过程中重新启动了部分效应生物学。持续的Stat5a活性能拮抗Tox，并重新连接CD8⁺ T细胞，使其从衰竭状态转变为持久的效应细胞和/或类似自然杀伤细胞（NK）的状态，具有更强的抗肿瘤潜力。使用正交的IL-2:IL2Rβ配对诱导Tex细胞中的Stat5活性可促进Tex^int细胞的积累，尤其是在PD-L1阻断后。重新激活Stat5还能部分重编程衰竭的表观遗传景观并恢复多功能性。这些数据凸显了操纵IL-2-Stat5轴以重新连接Tex细胞，使其处于更持久的保护状态的治疗机会。

附：英文原文

Title: Stat5 opposes the transcription factor Tox and rewires exhausted CD8+ T cells toward durable effector-like states during chronic antigen exposure

Author: Jean-Christophe Beltra, Mohamed S. Abdel-Hakeem, Sasikanth Manne, Zhen Zhang, Hua Huang, Makoto Kurachi, Leon Su, Lora Picton, Shin Foong Ngiow, Yuki Muroyama, Valentina Casella, Yinghui J. Huang, Josephine R. Giles, Divij Mathew, Jonathan Belman, Max Klapholz, Hélène Decaluwe, Alexander C. Huang, Shelley L. Berger, K. Christopher Garcia, E. John Wherry

Issue&Volume: 2023/12/12

Abstract: Rewiring exhausted CD8+ T (Tex) cells toward functional states remains a therapeutic challenge. Tex cellsare epigenetically programmed by the transcription factor Tox. However, epigeneticremodeling occurs as Tex cells transition from progenitor (Texprog) to intermediate (Texint) and terminal (Texterm) subsets, suggesting development flexibility. We examined epigenetic transitionsbetween Tex cell subsets and revealed a reciprocally antagonistic circuit betweenStat5a and Tox. Stat5 directed Texint cell formation and re-instigated partial effector biology during this Texprog-to-Texint cell transition. Constitutive Stat5a activity antagonized Tox and rewired CD8+ T cells from exhaustion to a durable effector and/or natural killer (NK)-like statewith superior anti-tumor potential. Temporal induction of Stat5 activity in Tex cellsusing an orthogonal IL-2:IL2Rβ-pair fostered Texint cell accumulation, particularly upon PD-L1 blockade. Re-engaging Stat5 also partiallyreprogrammed the epigenetic landscape of exhaustion and restored polyfunctionality.These data highlight therapeutic opportunities of manipulating the IL-2-Stat5 axisto rewire Tex cells toward more durably protective states.

DOI: 10.1016/j.immuni.2023.11.005

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00487-9