Malat1 is a Sex-Specific Determinant of Th Cell Differentiation

Understanding cell intrinsic mediators of sexual dimorphism in lymphocytes is critical to addressing differences in incidence and severity of immunopathologies between females and males. Here, we demonstrate that the nuclear speckle-associated lincRNA Malat1, one of the most highly abundant transcripts in mammalian cells, exerts a sex-specific function in Th2 differentiation by controlling early differentiation and endpoint cytokine expression in female cells. Malat1 deficiency impairs in vitro Th2 differentiation only in female mice, characterised by transcriptome-wide suppression of differentiation associated gene expression and cytokine expression, with particularly strong effects on IL10. Using an in vivo model of lung inflammation, we validated the sex-specific effects of Malat1 loss, demonstrating altered Th2 differentiation in both the lung and spleen for only female mice. Mechanistically, naïve T helper cells from Malat1-/- female mice demonstrate impaired early differentiation in the gene expression programme, along with upregulation of an interferon stimulated gene module associated with naïve CD4+ T cells. This is followed by suppression of the IL2 receptor, which in turn inhibits IL2 mediated differentiation. Male Th2 differentiation was less sensitive to effects of Malat1 loss due to stronger early activation, higher constitutive interferon responsive gene expression, and lower sensitivity to exogenous levels of IL2. Malat1 deficiency during early Th2 differentiation suppressed differentiation-associated changes in nuclear architecture in a sex-specific manner, with effects on nuclear speckle biogenesis, Xi complex localisation, and H3K27me3 deposition. Overall, this suggests that, despite neither being X/Y linked nor sex hormone responsive, Malat1 is a critical sex-specific regulator of Th cell differentiation, with profound implications in our understanding of how non-coding RNA drives immune sexual dimorphism.