A GPR174–CCL21 module imparts sexual dimorphism to humoral immunity

• Published in: Nature (London) 2020-01, Vol.577 (7790), p.416-420
• Main Authors: Zhao, Ruozhu, Chen, Xin, Ma, Weiwei, Zhang, Jinyu, Guo, Jie, Zhong, Xiu, Yao, Jiacheng, Sun, Jiahui, Rubinfien, Julian, Zhou, Xuyu, Wang, Jianbin, Qi, Hai
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/21; 13/31; 13/44; 13/51; 13/95; 14/19; 38/77; 631/250/2152/2153/1982; 631/250/98; 631/80/84/1372; Analysis; Animals; Antibodies; Antigens; Autoimmunity; B-Lymphocytes - immunology; Calcium; CCL21 protein; Cell adhesion & migration; Cell migration; Cell Movement; Cell receptors; Cells, Cultured; Chemokine CCL21 - genetics; Chemokine CCL21 - immunology; Chemokines; Chromosomes; Demographic aspects; Dimorphism; Dimorphism (Biology); Disease Susceptibility; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - immunology; Experimental allergic encephalomyelitis; Female; Females; Follicles; Fractionation; G protein-coupled receptors; G proteins; Germinal centers; Health aspects; Humanities and Social Sciences; Humoral immunity; Immune response (humoral); Immunity; Immunity, Humoral; Immunization; Ligands; Localization; Lymphocytes B; Lymphocytes T; Male; Males; Mice; Mice, Inbred C57BL; multidisciplinary; Organs; Physiological aspects; Positioning devices (machinery); Properties; Proteins; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - immunology; Science; Science (multidisciplinary); Scientific imaging; Sex Characteristics; Sexes; Sexual dimorphism; Testosterone
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1873-0

Humoral immune responses to immunization and infection and susceptibilities to antibody-mediated autoimmunity are generally lower in males 1 – 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. Male and female B cells show differing abilities to localize and contribute to germinal centres, in a way that depends on the G-protein-coupled guidance receptor GPR174 and its chemokine ligand CCL21.