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

Identifying cell intrinsic regulators of immune sexual dimorphism is critical for treatment of several immunopathologies. 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. Upon IL10R blockade a pronounced effect is also seen on IL4 and IL13. Mechanistically, naïve CD4 ⁺ T cells from Malat1 ^-/- female mice demonstrate altered early activation kinetics and impaired early differentiation gene expression, including up-regulation of an interferon stimulated gene (ISG) module. This is followed by suppression of IL2Rα and IL2Rγ expression and IL2-mediated differentiation. Mimicking the effect of Malat1 loss by maintaining early ISG expression in WT cells with IFNβ treatment partially phenocopies the effects of Malat1 deficiency. A subset of the effects of Malat1 loss in female cells is also observed in male cells. However, this does not affect endpoint Th2 differentiation. Male CD4 ⁺ T cells demonstrate stronger early activation, higher ISG expression during early differentiation, maintenance of IL2Rα expression independently of Malat1 , and lower sensitivity to exogenous IL2 during late differentiation compared to female cells. In vivo , female, but not male, Malat1 ^-/- mice demonstrate altered Th2 cytokine expression 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. Overall, these findings reveal Malat1 as a novel determinant of immune sexual dimorphism.