Estrogen Signaling in Bystander Foxp3 neg CD4 + T Cells Suppresses Cognate Th17 Differentiation in Trans and Protects from Central Nervous System Autoimmunity

Abstract 17β-Estradiol (E2) suppresses the development of experimental autoimmune encephalomyelitis (EAE) through estrogen receptor (ER) α, yet the cellular targets remain elusive. We have used an adoptive transfer model of myelin oligodendrocyte glycoprotein–specific CD4+ T cells from 2D2 TCR transgenic mice. We show that in the recipient mice, ERα expression in bystander CD4+ T cells, rather than in cognate 2D2 T cells, is required for the inhibition of Th17 cell differentiation by E2. Coadministration of estrogen-primed WT, but not ERα-deficient CD4+ T cells, with naive 2D2 T cells lacking ERα inhibited the development of Th17 cell–mediated EAE. Suppression of Th17 cells and protection f…