Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China.
La Jolla Institute for Immunology, La Jolla, CA.
J Exp Med. 2019 Jul 1;216(7):1664-1681. doi: 10.1084/jem.20190337. Epub 2019 May 23.
Follicular helper T (Tfh) cells are essential for germinal center formation and effective humoral immunity, which undergo different stages of development to become fully polarized. However, the detailed mechanisms of their regulation remain unsolved. Here we found that the E3 ubiquitin ligase VHL was required for Tfh cell development and function upon acute virus infection or antigen immunization. VHL acted through the hypoxia-inducible factor 1α (HIF-1α)-dependent glycolysis pathway to positively regulate early Tfh cell initiation. The enhanced glycolytic activity due to VHL deficiency was involved in the epigenetic regulation of ICOS expression, a critical molecule for Tfh development. By using an RNA interference screen, we identified the glycolytic enzyme GAPDH as the key target for the reduced ICOS expression via mA modification. Our results thus demonstrated that the VHL-HIF-1α axis played an important role during the initiation of Tfh cell development through glycolytic-epigenetic reprogramming.
滤泡辅助 T（Tfh）细胞对于生发中心的形成和有效的体液免疫至关重要，它们经历不同的发育阶段以完全极化。然而，其调节的详细机制仍未解决。在这里，我们发现 E3 泛素连接酶 VHL 在急性病毒感染或抗原免疫时，对于 Tfh 细胞的发育和功能是必需的。VHL 通过缺氧诱导因子 1α（HIF-1α）依赖性糖酵解途径发挥作用，正向调节早期 Tfh 细胞的起始。由于 VHL 缺陷导致的增强的糖酵解活性参与了 ICOS 表达的表观遗传调控，ICOS 是 Tfh 发育的关键分子。通过使用 RNA 干扰筛选，我们发现糖酵解酶 GAPDH 是通过 mA 修饰导致 ICOS 表达减少的关键靶标。因此，我们的研究结果表明，VHL-HIF-1α 轴通过糖酵解-表观遗传重编程在 Tfh 细胞发育的起始中发挥重要作用。
