PDF(Pubmed)
Abstract：
Rewiring exhausted CD8+ T (Tex) cells toward functional states remains a therapeutic challenge. Tex cells are epigenetically programmed by the transcription factor Tox. However, epigenetic remodeling occurs as Tex cells transition from progenitor (Texprog) to intermediate (Texint) and terminal (Texterm) subsets, suggesting development flexibility. We examined epigenetic transitions between Tex cell subsets and revealed a reciprocally antagonistic circuit between Stat5a 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 state with superior anti-tumor potential. Temporal induction of Stat5 activity in Tex cells using an orthogonal IL-2:IL2Rβ-pair fostered Texint cell accumulation, particularly upon PD-L1 blockade. Re-engaging Stat5 also partially reprogrammed the epigenetic landscape of exhaustion and restored polyfunctionality. These data highlight therapeutic opportunities of manipulating the IL-2-Stat5 axis to rewire Tex cells toward more durably protective states.
摘要：
将耗尽的CD8+T(Tex)细胞重新连接到功能状态仍然是治疗挑战。Tex细胞通过转录因子Tox进行表观遗传学编程。然而,表观遗传重塑发生在Tex细胞从祖细胞（Texprog）过渡到中间（Texint）和末端（Texterm）亚群时，建议开发灵活性。我们检查了Tex细胞亚群之间的表观遗传转变，并揭示了Stat5a和Tox之间的相互拮抗回路。Stat5指导Texint细胞形成，并在此Texprog到Texint细胞转变过程中重新激发了部分效应子生物学。组成型Stat5a活性拮抗Tox，并将CD8T细胞从耗尽重新连接为持久的效应子和/或自然杀伤（NK）样状态，具有出色的抗肿瘤潜力。使用正交IL-2：IL2Rβ对促进Texint细胞积累，在Tex细胞中对Stat5活性进行时间诱导，特别是在PD-L1阻断。重新参与Stat5还部分重新编程了耗竭和恢复多功能性的表观遗传景观。这些数据突出了操纵IL-2-Stat5轴以将Tex细胞重新连接到更持久的保护状态的治疗机会。
