A GPR174–CCL21 module imparts sexual dimorphism to humoral immunity

Ruozhu Zhao, Xin Chen, Weiwei Ma, Jinyu Zhang, Jie Guo, Xiu Zhong, Jiacheng Yao, Jiahui Sun, Julian Rubinfien, Xuyu Zhou, Jianbin Wang and Hai Qi ()
Additional contact information
Ruozhu Zhao: Tsinghua University
Xin Chen: Tsinghua University
Weiwei Ma: Tsinghua University
Jinyu Zhang: Tsinghua University
Jie Guo: Chinese Academy of Sciences
Xiu Zhong: Tsinghua University
Jiacheng Yao: Tsinghua University
Jiahui Sun: Tsinghua University
Julian Rubinfien: Tsinghua University
Xuyu Zhou: Chinese Academy of Sciences
Jianbin Wang: Tsinghua University
Hai Qi: Tsinghua University

Nature, 2020, vol. 577, issue 7790, 416-420

Abstract: Abstract Humoral immune responses to immunization and infection and susceptibilities to antibody-mediated autoimmunity are generally lower in males1–3. However, the mechanisms underlying such sexual dimorphism are not well understood. Here we show that there are intrinsic differences between the B cells that produce germinal centres in male and female mice. We find that antigen-activated male B cells do not position themselves as efficiently as female B cells in the centre of follicles in secondary lymphoid organs, in which germinal centres normally develop. Moreover, GPR174—an X-chromosome-encoded G-protein-coupled receptor—suppresses the formation of germinal centres in male, but not female, mice. This effect is intrinsic to B cells, and correlates with the GPR174-enhanced positioning of B cells towards the T-cell–B-cell border of follicles, and the distraction of male, but not female, B cells from S1PR2-driven follicle-centre localization. Biochemical fractionation of conditioned media that induce B-cell migration in a GPR174-dependent manner identifies CCL21 as a GPR174 ligand. In response to CCL21, GPR174 triggers a calcium flux and preferentially induces the migration of male B cells; GPR174 also becomes associated with more Gαi protein in male than in female B cells. Male B cells from orchidectomized mice exhibit impaired GPR174-mediated migration to CCL21, and testosterone treatment rescues this defect. Female B cells from testosterone-treated mice exhibit male-like GPR174–Gαi association and GPR174-mediated migration. Deleting GPR174 from male B cells causes more efficient positioning towards the follicular centre, the formation of more germinal centres and an increased susceptibility to B-cell-dependent experimental autoimmune encephalomyelitis. By identifying GPR174 as a receptor for CCL21 and demonstrating its sex-dependent control of B-cell positioning and participation in germinal centres, we have revealed a mechanism by which B-cell physiology is fine-tuned to impart sexual dimorphism to humoral immunity.

Date: 2020
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DOI: 10.1038/s41586-019-1873-0

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