Post doctoral researcher Northwestern Univ. Feinberg Sch. of Med. Chicago, Illinois, United States
Disclosure(s):
MIJIN KIM, PhD: No financial relationships to disclose
Introduction/Rationale: 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. IFN 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.
