<i>Malat1</i> regulates female Th2 cell cytokine expression through controlling early differentiation and response to IL-2

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 T helper 2 (Th2) cells. Malat1 deficiency impairs in vitro Th2 differentiation of naïve CD4+ T cells from female mice, characterized by transcriptome-wide effects and suppression of cytokine expression, particularly interleukin (IL)-10. Upon IL-10 receptor (IL10R) blockade a pronounced effect is also seen on IL-4 and IL-13. Mechanistically, naïve CD4+ T cells from Malat1-/- female mice demonstrate altered early activation kinetics and impaired early differentiation gene expression, including upregulation of an interferon-stimulated gene (ISG) module. This is followed by suppression of IL2Rα and IL2Rγ expression and IL-2-mediated differentiation. Mimicking the effect of Malat1 loss by maintaining early ISG expression in WT cells with interferon β 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 IL-2 during late differentiation compared with female cells. In vivo, female, but not male, Malat1-/- mice demonstrate altered Th2 cytokine expression characterized by a reduction in IL-10+ 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.