Proc. Natl. Acad. Sci. USA https://doi.org/10.1073/pnas.1710401115 (2018)

There is a well-known skewing in the incidence and severity of multiple sclerosis in human females, a relationship that is reflected in at least some strains of mice. In The Proceedings of the National Academy of Sciences USA, Brown and colleagues use an SJL mouse model of experimental autoimmune encephalitis to explore the mechanistic basis of this sex difference in disease susceptibility. After immunization with myelin peptide, female mice have a greater abundance of encephalitogenic cells of the TH17 subset of helper T cells, whereas male mice show a more protective type 2–shifted immunity. Mechanistically, testosterone acts on mast cells, which in turn produce the cytokine IL-33 that drives the activation of type 2 innate lymphoid cells. The absolute amount of testosterone is not the only factor in play; instead, male mouse–derived mast cells show an intrinsically greater proclivity to produce IL-33.