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Article
female μMT:Gpr174−/− bone-marrow (80/20) chimaeras with human
MOG1–120 protein and followed the disease course. All mice developed
symptoms of EAE, with females suffering a more severe disease course;
GPR174 deletion did not change the disease course in females but did
exacerbate it in males (Fig. 4a). Correlating with this finding, male
μMT:Gpr174+/y chimaeras produced the lowest MOG1–120-specific anti-
body titres, which were increased in male μMT:Gpr174−/y chimaeras
to a level similar to that in females (Fig. 4b). Therefore, the sexually
dimorphic functions of GPR174 in B cells contribute substantially to
different disease susceptibilities in the two sexes.
Our study identifies GPR174 as a receptor for CCL21, and reveals its
chemotactic effects on activated B cells as a mechanism for sexual
dimorphism in humoral responses and autoimmunity. Testosterone-
conditioned differential coupling to Gαi proteins underlies the different
effects of GPR174 on male and female B-cell migration to CCL21. Given
the well-established role of CCR7 in CCL21-mediated chemotaxis, it is an
intriguing possibility that CCL21 binding might induce GPR174–CCR7
heterodimerization and achieve a signalling outcome that these two
receptors cannot attain individually. When CCR7 is ablated in B cells,
CCL21-induced GPR174–Gαi coupling and GPR174-mediated migration
are markedly reduced (R.Z. et al., unpublished observations), suggest-
ing a dual role for CCR7 in governing the B-cell migratory response
to CCL21 via itself and GPR174. LysoPS restrains regulatory T cells in a
GPR174-dependent manner^13. Future studies will need to elucidate how
tripartite CCL21–GPR174–CCR7 interactions regulate Gαi coupling and
downstream signals in a testosterone-dependent manner, and whether
and how LysoPS and CCL21 might compete or collaborate in trigger-
ing GPR174-dependent functions. Although the functions of GPR174
in humans remain to be validated, antagonists that selectively target
GPR174 binding to CCL21 or selectively inhibit GPR174–Gαi coupling
in B cells might boost vaccine outcomes in otherwise poorly respond-
ing men.
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