Targeting Impaired Type I Interferon-IL-27 Signaling Rescues T Regulatory Cell Suppressive Function in...

Area of Science:

• Immunology
• Neuroimmunology
• Cellular and Molecular Medicine

Background:

• T regulatory cells (Tregs) are crucial for immune homeostasis.
• Tregs from relapsing-remitting multiple sclerosis (RRMS) patients exhibit impaired suppressive function.
• The molecular mechanisms underlying RRMS Treg dysfunction are not fully understood, particularly regarding type I interferon (IFN) and IL-27 signaling pathways.

Purpose of the Study:

• To investigate the molecular mechanisms of Treg dysfunction in RRMS.
• To explore the therapeutic potential of targeting IFN and IL-27 signaling pathways to restore Treg function in RRMS.
• To evaluate the efficacy of cGAMP-loaded microparticles (MPs) in ameliorating experimental autoimmune encephalomyelitis (EAE) by modulating Treg function.

Main Methods:

• Single-cell RNA sequencing (scRNAseq) of Tregs from RRMS patients and healthy controls (HCs).
• Treatment of EAE model with cGAMP-MPs to activate the stimulator of IFN genes (STING) pathway.
• Genetic manipulation using Treg-specific IL-27R knockout mice (Treg ΔIl27ra).
• In vitro IL-27 stimulation of RRMS-derived Tregs.

Main Results:

• RRMS Tregs display down-regulation of type I IFN and IL-27 signaling pathways, with reduced expression of IFN-stimulated genes (ISGs) and key Treg suppressive mediators.
• cGAMP-MP treatment ameliorated EAE by inducing Tregs expressing IL-27R, IL-10, TGF-b, and Granzyme B.
• The therapeutic effect of cGAMP-MP treatment in EAE was dependent on IL-27 signaling, as it was abolished in Treg ΔIl27ra mice.
• In vitro IL-27 stimulation restored the expression of IFN pathway genes and Treg suppressive genes in RRMS Tregs.

Conclusions:

• Decreased type I IFN and IL-27 signaling contribute to Treg dysfunction in RRMS.
• Activating the STING pathway with cGAMP-MPs can restore Treg suppressive function and ameliorate EAE, highlighting the role of IL-27 signaling.
• IL-27 pre-stimulation holds promise for restoring Treg suppressive function and enhancing their migration to the central nervous system (CNS) in future clinical applications for RRMS.