Foxo3 Promotes the Differentiation and Function of Follicular Helper T Cells

Haiyu Qi; Dan Tian; Mingyang Li; Chunpan Zhang; Hua Jin; Liwei Liu; Xinyan Zhao; Linlin Ma; Weijia Zhao; Qing Ge; Ting Duan; Dong Zhang

doi:10.1016/j.celrep.2020.107621

Foxo3 Promotes the Differentiation and Function of Follicular Helper T Cells

Cell Rep. 2020 May 12;31(6):107621. doi: 10.1016/j.celrep.2020.107621.

Authors

Haiyu Qi¹, Dan Tian², Mingyang Li², Chunpan Zhang², Hua Jin², Liwei Liu³, Xinyan Zhao³, Linlin Ma⁴, Weijia Zhao⁵, Qing Ge⁵, Ting Duan⁶, Dong Zhang⁷

Affiliations

¹ Department of Rheumatology and Immunology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
² Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China.
³ National Clinical Research Center for Digestive Diseases, Beijing 100050, China.
⁴ Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
⁵ Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
⁶ Department of Rheumatology and Immunology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China. Electronic address: duanting888888@126.com.
⁷ Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China; General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China. Electronic address: zhangd@ccmu.edu.cn.

PMID: 32402289
DOI: 10.1016/j.celrep.2020.107621

Abstract

Follicular helper T cells (Tfhs) are essential for germinal center (GC) B cell maturation and antibody development. However, the intrinsic mechanisms that regulate Tfh differentiation are largely unknown. Here, we demonstrate that the frequencies of Tfhs and GC B cells, as well as interleukin-21 (IL-21) and anti-ovalbumin (OVA) antibodies, are markedly decreased in forkhead box O3 (Foxo3) knockout mice immunized with OVA. Using mixed bone marrow chimeras and lymphocyte-repopulated Rag1^-/- mice proves that wild-type (WT), but not Foxo3-deficient T cells provoke GC B cell maturation and antibody production. Deficiency of Foxo3 inhibits inducible T cell co-stimulator (ICOS)-induced Tfh differentiation. Chromatin immunoprecipitation assay results suggest that Foxo3 is able to bind to the IL-21 promoter and regulate IL-21 secretion. In conclusion, our study unveils a critical role of Foxo3 in the regulation of Tfh differentiation and IL-21 production. Modulating Foxo3 activity may be beneficial for enhancing or preventing antibody-mediated immune responses.

Keywords: Foxo3; IL-21; Inducible T-cell Costimulator; T follicular helper cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / immunology
Forkhead Box Protein O3 / deficiency
Forkhead Box Protein O3 / immunology*
Immunity, Humoral
Inducible T-Cell Co-Stimulator Protein / antagonists & inhibitors
Inducible T-Cell Co-Stimulator Protein / immunology
Interleukin-21 Receptor alpha Subunit / genetics
Interleukin-21 Receptor alpha Subunit / immunology
Male
Mice
Mice, Knockout
Promoter Regions, Genetic
T Follicular Helper Cells / cytology
T Follicular Helper Cells / immunology*

Substances

Forkhead Box Protein O3
FoxO3 protein, mouse
Il21r protein, mouse
Inducible T-Cell Co-Stimulator Protein
Interleukin-21 Receptor alpha Subunit