The role of interferon-stimulated gene IFIT2 in a sex-dependent Treg modulation in CNS autoimmunity 2267558
Year: 2026
Type: article
Abstract: Introduction Foxp3+ regulatory T (Treg) cells are essential for maintaining immune regulation and homeostasis by preventing excessive immune activation in autoimmunity, such as multiple sclerosis (MS). However, the mechanisms that control Treg function remain largely unknown. Type I IFN signaling serves as an important immune modulator in MS pathogenesis. We previously reported that IFIT2 (interferon-induced proteins with tetratricopeptide repeats), one of the IFN-stimulated genes, limits autoimmune inflammation by promoting myelin debris clearance and remyelination. Here, we investigated whether IFIT2 plays a role in Treg functions to suppress autoimmune inflammation. Methods We used germline and a novel Treg-specific IFIT2-/- mouse models and RNAseq analysis to examine the role of IFIT2 in Treg function in experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. Results We found that IFIT2 controls Treg suppressive functions and metabolic profiles selectively in males. Ifit2-/- Tregs exhibited higher glycolysis and lower oxidative phosphorylation, hallmarks of functionally defective Tregs. Bulk RNA-seq analysis further confirmed that Myc and mTORC1 signaling pathways are highly enriched in KO cells. IFNβ stimulation enhances Treg functions and regulates Treg metabolism. However, IFNβ-induced metabolic changes and suppressive activity were completely lost in Ifit2-/- Tregs. At the molecular level, IFIT2 expression was required for Treg expression of PPARα, a ligand-activated transcription factor involved in cellular metabolism. Interestingly, IFNβ-induced, IFIT2-dependent PPARα expression was observed only in male Tregs, or in testosterone-treated female Tregs. Conclusion Together, this study reports a novel function of IFIT2 by which IFNβ signaling controls Treg metabolic activity and suppressive functions through the IFIT2-PPARa axis-dependent and sex-dimorphic manner in autoimmune inflammation. Funding Source NIAID Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)
Source: The Journal of Immunology
Authors: Mijin Kim, Dongkyun Kim, Booki Min
Institution: Northwestern University
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W7171521071
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