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

被引:80
作者
Zhu, Yangyang [1 ]
Zhao, Yanxia [1 ]
Zou, Le [1 ]
Zhang, Danfeng [1 ]
Aki, Daisuke [1 ,2 ]
Liu, Yun-Cai [1 ,2 ]
机构
[1] Tsinghua Univ, Sch Med, Tsinghua Peking Ctr Life Sci, Inst Immunol, Beijing, Peoples R China
[2] La Jolla Inst Immunol, La Jolla, CA 92037 USA
基金
中国国家自然科学基金;
关键词
CXC CHEMOKINE RECEPTOR-5; GERMINAL CENTER HYPOXIA; B-CELLS; METABOLISM; EXPRESSION; T-HELPER-1; REGULATORS; REPRESSES; RESPONSES; DEFINES;
D O I
10.1084/jem.20190337
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:1664 / 1681
页数:18
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