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Oestrogen treatment of experimental autoimmune encephalomyelitis requires 17β‐oestradiol‐receptor‐positive B cells that up‐regulate PD‐1 on CD4+ Foxp3+ regulatory T cells

It is now well accepted that sex hormones have immunoregulatory activity and may prevent exacerbations in multiple sclerosis during pregnancy. Our previous studies demonstrated that oestrogen (17β‐oestradiol; E2) protection against experimental autoimmune encephalomyelitis (EAE) is mediated mainly through oestrogen receptor‐α (ERα) and the membrane receptor G‐protein‐coupled receptor 30 (GPR30) and is abrogated in the absence of B cells and the co‐inhibitory receptor, Programmed Death‐1 (PD‐1). To critically evaluate the cell source of the E2 and PD‐1 co‐inhibitory pathways in EAE regulation, we assessed the requirement for ERs on transferred B cells and downstream effects on expression of PD‐1/PD‐ligand on CD4+ Foxp3+ regulatory T (Treg) cells in B‐cell‐replenished, E2‐treated B‐cell‐deficient (μMT−/−) mice with EAE. The results clearly demonstrated involvement of ERα and GPR30 on transferred B cells that mediated the protective E2 treatment effect on EAE and further showed an E2‐mediated B‐cell‐dependent up‐regulation of PD‐1 on CD4+ Foxp3+ Treg cells. These findings identify regulatory B‐cell populations as key players in potentiating Treg‐cell activity during E2‐mediated protection against EAE.