Volume 34, No 4, Apr 2024

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 34 Issue 4, April 2024: 295-308   |  Open Access

ORIGINAL ARTICLES

B cell-reactive triad of B cells, follicular helper and regulatory T cells at homeostasis

Yihan Lin^1,2,3,† , Zurong Wan^1,2,3,12,† , Bo Liu^1,2,3,4,† , Jiacheng Yao^4,5,† , Tianqi Li⁵ , Fang Yang⁶ , Jianhua Sui⁶ , Yongshan Zhao^1,2,3 , Wanli Liu⁵ , Xuyu Zhou⁷ , Jianbin Wang^4,5,†,* , Hai Qi^{1,2,3,4,8,9,10,11,†,*}

¹Tsinghua-Peking Center for Life Sciences, Beijing, China
²Laboratory of Dynamic Immunobiology, Institute for Immunology, Tsinghua University, Beijing, China
³Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
⁴Changping Laboratory, Beijing, China
⁵School of Life Sciences, Tsinghua University, Beijing, China
⁶National Institute of Biological Sciences, Beijing, China
⁷Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
⁸New Cornerstone Science Laboratory, School of Medicine, Tsinghua University, Beijing, China
⁹Beijing Key Laboratory for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China
¹⁰Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China
¹¹SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, Shanxi, China
¹²Present address: Weill Cornell Medical College, Cornell University, Ithaca, NY, USA
^†These authors contributed equally: Yihan Lin, Zurong Wan, Bo Liu, Jiacheng Yao
^†These authors jointly supervised this work: Jianbin Wang, Hai Qi
Correspondence: Jianbin Wang(jianbinwang@tsinghua.edu.cn)Hai Qi(qihai@tsinghua.edu.cn)

Autoreactive B cells are silenced through receptor editing, clonal deletion and anergy induction. Additional autoreactive B cells are ignorant because of physical segregation from their cognate autoantigen. Unexpectedly, we find that follicular B cell-derived autoantigen, including cell surface molecules such as FcγRIIB, is a class of homeostatic autoantigen that can induce spontaneous germinal centers (GCs) and B cell-reactive autoantibodies in non-autoimmune animals with intact T and B cell repertoires. These B cell-reactive B cells form GCs in a manner dependent on spontaneous follicular helper T (TFH) cells, which preferentially recognize B cell-derived autoantigen, and in a manner constrained by spontaneous follicular regulatory T (TFR) cells, which also carry specificities for B cell-derived autoantigen. B cell-reactive GC cells are continuously generated and, following immunization or infection, become intermixed with foreign antigen-induced GCs. Production of plasma cells and antibodies derived from B cell-reactive GC cells are markedly enhanced by viral infection, potentially increasing the chance for autoimmunity. Consequently, immune homeostasis in healthy animals not only involves classical tolerance of silencing and ignoring autoreactive B cells but also entails a reactive equilibrium attained by a spontaneous B cell-reactive triad of B cells, TFH cells and TFR cells.

https://doi.org/10.1038/s41422-024-00929-0

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