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J Exp Med. 2019 Jul 1;216(7):1664-1681. doi: 10.1084/jem.20190337. Epub 2019 May 23.

The E3 ligase VHL promotes follicular helper T cell differentiation via glycolytic-epigenetic control.

Author information

1
Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China.
2
La Jolla Institute for Immunology, La Jolla, CA.
3
Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China yuncai_liu@mail.tsinghua.edu.cn.

Abstract

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 m6A 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.

PMID:
31123085
PMCID:
PMC6605754
[Available on 2020-01-01]
DOI:
10.1084/jem.20190337

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