Follicular helper T (T_FH) cells are a specialized subset of CD4⁺ T cells that essentially support germinal center responses where high-affinity and long-lived humoral immunity is generated. The regulation of T_FH cell survival remains unclear. Here we report that T_FH cells show intensified lipid peroxidation and altered mitochondrial morphology, resembling the features of ferroptosis, a form of programmed cell death that is driven by iron-dependent accumulation of lipid peroxidation. Glutathione peroxidase 4 (GPX4) is the major lipid peroxidation scavenger and is necessary for T_FH cell survival. The deletion of GPX4 in T cells selectively abrogated T_FH cells and germinal center responses in immunized mice. Selenium supplementation enhanced GPX4 expression in T cells, increased T_FH cell numbers and promoted antibody responses in immunized mice and young adults after influenza vaccination. Our findings reveal the central role of the selenium–GPX4–ferroptosis axis in regulating T_FH homeostasis, which can be targeted to enhance T_FH cell function in infection and following vaccination.

滤泡辅助 T (T _FH ) 细胞是 CD4 ⁺ T 细胞的一个特化子集，主要支持生发中心反应，产生高亲和力和长寿命的体液免疫。T _FH细胞存活的调节仍不清楚。在这里，我们报告 T _FH细胞表现出强化的脂质过氧化和改变的线粒体形态，类似于铁死亡的特征，这是一种由铁依赖性脂质过氧化积累驱动的程序性细胞死亡形式。谷胱甘肽过氧化物酶 4 (GPX4) 是主要的脂质过氧化清除剂，是 T _FH细胞存活所必需的。T细胞中GPX4的缺失选择性地消除了T _FH免疫小鼠的细胞和生发中心反应。硒补充剂增强了 T 细胞中 GPX4 的表达，增加了 T _FH细胞数量并促进了免疫小鼠和年轻成人在流感疫苗接种后的抗体反应。我们的研究结果揭示了硒-GPX4-ferroptosis 轴在调节 T _FH稳态中的核心作用，可以针对增强 T _FH细胞在感染和接种疫苗后的功能。