During persistent antigen stimulation, exhausted CD8 + T cells are continuously replenished by self-renewing stem-like T cells. However, how CD8 + T cells adapt to chronic stimulation remains unclear. Here, we show that persistent antigen stimulation primes chromatin for regulation by the redox-sensing KEAP1-NRF2 pathway. Loss of KEAP1 in T cells impaired control of chronic viral infection. T cell–intrinsic KEAP1 suppressed NRF2 to promote expansion and persistence of virus-specific CD8 + T cells, drive a stem-like T cell response, down-regulate immune checkpoint molecules, and limit T cell receptor (TCR) hyperactivation and apoptosis. NRF2 epigenetically derepressed BACH2 targets and opposed a stem-like program driven by BACH2. In exhausted T cells induced by tonic GD2 chimeric antigen receptor (CAR) signaling, the effects of KEAP1 deficiency were rescued by inhibiting proximal TCR signaling. Enhancing mitochondrial oxidation improved the expansion and survival of KEAP1-deficient CD8 + GD2 CAR T cells and up-regulated markers associated with stem-like cells. Thus, the KEAP1-NRF2 axis regulates stem-like CD8 + T cells and long-term T cell immunity during chronic antigen exposure.

中文翻译：

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氧化还原传感器 KEAP1 通过防止过度激活来促进 T 细胞对慢性抗原刺激的适应


在持续抗原刺激期间，耗竭的 CD8 + T 细胞由自我更新的干细胞样 T 细胞不断补充。然而，CD8 + T 细胞如何适应慢性刺激仍不清楚。在这里，我们表明持续抗原刺激使染色质受到氧化还原感应 KEAP1-NRF2 通路的调节。T 细胞中 KEAP1 的缺失会损害对慢性病毒感染的控制。T 细胞内在的 KEAP1 抑制 NRF2 以促进病毒特异性 CD8 + T 细胞的扩增和持久性，驱动干细胞样 T 细胞反应，下调免疫检查点分子，并限制 T 细胞受体 （TCR） 过度激活和细胞凋亡。NRF2 表观遗传去抑制 BACH2 靶标并对抗由 BACH2 驱动的茎样程序。在强直性 GD2 嵌合抗原受体 （CAR） 信号传导诱导的耗竭 T 细胞中，通过抑制近端 TCR 信号传导来挽救 KEAP1 缺陷的作用。增强线粒体氧化改善了 KEAP1 缺陷型 CD8 + GD2 CAR T 细胞的扩增和存活，并上调了与干细胞样细胞相关的标志物。因此，KEAP1-NRF2 轴在慢性抗原暴露期间调节干细胞样 CD8 + T 细胞和长期 T 细胞免疫。