Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University, Göttingen, Germany.
Elife. 2023 May 11;12:e84280. doi: 10.7554/eLife.84280.
Oxygenation levels are a determinative factor in T cell function. Here, we describe how oxygen tensions sensed by mouse and human T cells at the moment of activation act to persistently modulate both differentiation and function. We found that in a protocol of CAR-T cell generation, 24 hr of low oxygen levels during initial CD8 T cell priming is sufficient to enhance antitumour cytotoxicity in a preclinical model. This is the case even when CAR-T cells are subsequently cultured under high oxygen tensions prior to adoptive transfer. Increased hypoxia-inducible transcription factor (HIF) expression was able to alter T cell fate in a similar manner to exposure to low oxygen tensions; however, only a controlled or temporary increase in HIF signalling was able to consistently improve cytotoxic function of T cells. These data show that oxygenation levels during and immediately after T cell activation play an essential role in regulating T cell function.
氧合水平是 T 细胞功能的决定因素。在这里，我们描述了在激活时，小鼠和人类 T 细胞感知到的氧张力如何持续调节分化和功能。我们发现，在 CAR-T 细胞生成方案中，在初始 CD8 T 细胞启动期间低氧水平持续 24 小时足以增强临床前模型中的抗肿瘤细胞毒性。即使 CAR-T 细胞随后在过继转移前在高氧张力下培养也是如此。增加缺氧诱导转录因子 (HIF) 的表达能够以类似于暴露于低氧张力的方式改变 T 细胞命运;然而，只有 HIF 信号的受控或短暂增加才能一致改善 T 细胞的细胞毒性功能。这些数据表明，T 细胞激活期间和之后的氧合水平在调节 T 细胞功能方面起着至关重要的作用。
