Sex-hormone receptors pattern on regulatory T-cells: clinical implications for multiple sclerosis

Cellular mechanisms underlying sexual dimorphism in the immune response remain largely unknown. Concerning the interactions among the nervous, endocrine and immune systems, we reported that during gestation, a period during which multiple sclerosis (MS) clearly ameliorates, there is a physiological expansion of regulatory T-lymphocytes (T_Reg). Given that alterations in T_Reg proportions and suppressive function are involved in MS pathophysiology, we investigated the in vitro effect of sex hormones on T_Reg. Here, we show that both E2 and progesterone (P2) enhance T_Reg function in vitro, although only E2 further induces a T_Reg phenotype in activated responder T-cells (CD4⁺CD25⁻) (P < 0.01). E2 receptor beta (ERβ) percentages and mean fluorescence intensity (MFI) on T_Reg were lower in MS patients than in controls (P < 0.05), in parallel with lower E2 plasma levels (P < 0.05). Importantly, percentages and MFI of ERβ were higher in T_Reg than in T-responder cells (P < 0.0001) both in MS patients and controls. We show a unique differential pattern of higher ER and PR levels in T_Reg, which may be relevant for the in vivo responsiveness of these cells to sex hormones and hence to MS physiopathology.