W124 - Sex Bias in Tr1 Differentiation and IL-10 Production: Role of PI3K Signaling in Multiple Sclerosis

Abstract Text: Multiple sclerosis (MS) is a chronic inflammatory disease with a higher prevalence in females. T cells are key in MS, with CD46 converting Th1 cells into type 1 regulatory T cells (Tr1). This pathway is impaired in MS, reducing IL-10 production. The relationship between sex and Tr1 differentiation remains unexplored.

Our data show a sex bias in Tr1 differentiation upon CD46 activation in healthy donors. Female CD46-induced Tr1 cells produced lower levels of IL-10 and IFN-g, with reduced c-MAF expression, compared to males. This sex bias was not restricted to the CD46 pathway, as a similar sex bias was observed in IL-27-induced Tr1 cells. As it was previously shown that PI3K pathway inhibition in IL-27-induced-Tr1 cells inhibited IL-10 secretion in mice, we examined the role of this pathway in human Tr1 cells. Surprisingly, we observed an antagonistic role for PI3K depending on the Tr1 induction pathways, as well as a sex bias in the response to inhibition. While PI3K inhibition decreased IL-10 production by IL-27-induced Tr1 cells, it increased IL-10 production in CD46-mediated Tr1 cells, with a stronger effect in females. Differences in PI3K pathway could explain the sex-based difference in IL-10 production. Interestingly, the sex bias in CD46-induced Tr1 cells was not observed in people with MS. However, PI3K inhibition restored IL-10 production in both sexes, suggesting potential new therapeutic strategies.

Overall, our data demonstrate that sex regulates IL-10 production by CD46-induced Tr1 cells through the PI3K pathway, potentially contributing to female susceptibility to MS and autoimmune diseases.