Gwynne, Mags, West, Katie A, van Dongen, Stijn et al. (6 more authors) (2025) Malat1 regulates female Th2 cell cytokine expression through controlling early differentiation and response to IL-2. Journal of Immunology. vkaf177. ISSN: 1550-6606
Abstract
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2025. Published by Oxford University Press on behalf of The American Association of Immunologists. |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Hull York Medical School (York) The University of York > Faculty of Sciences (York) > Biology (York) |
Depositing User: | Pure (York) |
Date Deposited: | 02 Sep 2025 16:40 |
Last Modified: | 20 Sep 2025 02:27 |
Published Version: | https://doi.org/10.1093/jimmun/vkaf177 |
Status: | Published online |
Refereed: | Yes |
Identification Number: | 10.1093/jimmun/vkaf177 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:231131 |