Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Front Immunol. 2024 Apr 16;15:1293723. doi: 10.3389/fimmu.2024.1293723. eCollection 2024.
T cells must adapt to variations in tissue microenvironments; these adaptations include the degree of oxygen availability. The hypoxia-inducible factor (HIF) transcription factors control much of this adaptation, and thus regulate many aspects of T cell activation and function. The HIFs are in turn regulated by oxygen-dependent hydroxylases: both the prolyl hydroxylases (PHDs) which interact with the VHL tumour suppressor and control HIF turnover, and the asparaginyl hydroxylase known as the Factor inhibiting HIF (FIH), which modulates HIF transcriptional activity. To determine the role of this latter factor in T cell function, we generated T cell-specific FIH knockout mice. We found that FIH regulates T cell fate and function in a HIF-dependent manner and show that the effects of FIH activity occur predominantly at physiological oxygen concentrations. T cell-specific loss of FIH boosts T cell cytotoxicity, augments T cell expansion , and improves anti-tumour immunotherapy in mice. Specifically inhibiting FIH in T cells may therefore represent a promising strategy for cancer immunotherapy.
T 细胞必须适应组织微环境的变化；这些适应包括氧气供应的程度。缺氧诱导因子 (HIF) 转录因子控制着这种适应的大部分，从而调节 T 细胞激活和功能的许多方面。HIFs 反过来又受到氧依赖性羟化酶的调节：与 VHL 肿瘤抑制因子相互作用并控制 HIF 周转率的脯氨酰羟化酶 (PHD)，以及调节 HIF 转录活性的天冬酰胺羟化酶，称为 HIF 抑制因子 (FIH)。为了确定后者在 T 细胞功能中的作用，我们生成了 T 细胞特异性 FIH 敲除小鼠。我们发现 FIH 以 HIF 依赖的方式调节 T 细胞命运和功能，并表明 FIH 活性的影响主要发生在生理氧浓度下。T 细胞特异性缺失 FIH 可增强 T 细胞的细胞毒性，增强 T 细胞扩增，并改善小鼠的抗肿瘤免疫治疗。因此，特异性抑制 T 细胞中的 FIH 可能代表癌症免疫治疗的一种有前途的策略。
