Malat1 regulates female Th2 cell cytokine expression through controlling early differentiation and response to IL2

Beyond sex hormone and sex chromosome-driven mechanisms, little is known about cell intrinsic mediators of immune sexual dimorphism. We show that Malat1 is required for appropriate cytokine expression in female but not male Th2 cells. Malat1 deficiency impairs in vitro Th2 differentiation of naïve CD4 ⁺ T cells from female mice, characterised by transcriptome-wide effects and suppression of cytokine expression, particularly IL10. Mechanistically, naïve CD4 ⁺ T cells from Malat1 ^−/− female mice demonstrate altered early activation kinetics, followed by impairment of the early differentiation gene expression programme, including up-regulation of an interferon responsive gene module. This is followed by suppression of IL2Rα and IL2Rγ expression and IL2-mediated differentiation. Male CD4 ⁺ T cell activation and Th2 differentiation are not sensitive to Malat1 loss due to stronger early activation, higher interferon responsive gene expression during early differentiation, maintenance of IL2Rα expression independently of Malat1 , and lower sensitivity to exogenous IL2 during late differentiation. In vivo female, but not male, Malat1 ^−/− mice demonstrate altered Th2 differentiation characterised by a reduction in IL10 ⁺ Th2 cells in both lung and spleen following priming and challenge with Schistosoma mansoni eggs, a model of lung type 2 inflammation. These findings reveal Malat1 as a determinant of immune sexual dimorphism.