期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 216, 期 7, 页码 1664-1681出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20190337
关键词
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资金
- Ministry of Science and Technology of China [YFA0505802, YFC0903900]
- National Natural Science Foundation of China [NSFC81630041]
- Tsinghua-Peking Center for Life Sciences
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 1 alpha (HIF-1 alpha)-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 m(6)A modification. Our results thus demonstrated that the VHL-HIF-1 alpha axis played an important role during the initiation of Tfh cell development through glycolytic-epigenetic reprogramming.
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