Vitamin D and estrogen synergy in Vdr-expressing CD4⁺ T cells is essential to induce Helios⁺FoxP3⁺ T cells and prevent autoimmune demyelinating disease

Multiple sclerosis (MS) is a neurodegenerative disease resulting from an autoimmune attack on the axon-myelin unit. A female MS bias becomes evident after puberty and female incidence has tripled in the last half-century, implicating a female sex hormone interacting with a modifiable environmental factor. These aspects of MS suggest that many female MS cases may be preventable. Mechanistic knowledge of this hormone-environment interaction is needed to devise strategies to reduce female MS risk. We previously demonstrated that vitamin D₃ (D3) deficiency increases and D3 supplementation decreases experimental autoimmune encephalomyelitis (EAE) risk in a female-biased manner. We also showed that D3 acts in an estrogen (E2)-dependent manner, since ovariectomy eliminated and E2 restored D3-mediated EAE protection. Here we probed the hypothesis that E2 and D3 interact synergistically within CD4⁺ T cells to control T cell fate and prevent demyelinating disease. The E2 increased EAE resistance in wild-type (WT) but not T-Vdr⁰ mice lacking Vdr gene function in CD4⁺ T cells, so E2 action depended entirely on Vdr⁺CD4⁺ T cells. The E2 levels were higher in WT than T-Vdr⁰ mice, suggesting the Vdr⁺CD4⁺ T cells produced E2 or stimulated its production. The E2 decreased Cyp24a1 and increased Vdr transcripts in T cells, prolonging the calcitriol half-life and increasing calcitriol responsiveness. The E2 also increased CD4⁺Helios⁺FoxP3⁺ T regulatory (Treg) cells in a Vdr-dependent manner. Thus, CD4⁺ T cells have a cooperative amplification loop involving E2 and calcitriol that promotes CD4⁺Helios⁺FoxP3⁺ Treg cell development and is disrupted when the D3 pathway is impaired. The global decline in population D3 status may be undermining a similar cooperative E2-D3 interaction controlling Treg cell differentiation in women, causing a breakdown in T cell self tolerance and a rise in MS incidence.