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 (ER beta) 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 ER beta 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.