Host-derived mannose glycans trigger a pathogenic γδ T cell/IL-17a axis in autoimmunity

Area of Science:

• Immunology
• Glycobiology
• Autoimmune Diseases

Background:

• Autoimmune diseases like Systemic Lupus Erythematosus (SLE) involve immune system self-tolerance breakdown.
• Altered protein glycosylation is linked to autoimmune disease, but mechanisms remain unclear.
• Microbial glycans may trigger autoreactive immune responses.

Purpose of the Study:

• To investigate the role of microbial-associated mannose structures in kidney autoimmunity.
• To elucidate the mechanisms linking glycan structures to T cell activation and autoimmune responses.
• To explore glycometabolic reprogramming as a therapeutic strategy for autoimmune diseases.

Main Methods:

• Analysis of kidney-associated mannose structures and DC-SIGN-expressing γδ T cells.
• Utilizing mice lacking Mgat5 to study the impact of altered glycosylation on autoimmune development.
• Investigating the effects of N-acetylglucosamine supplementation on T cell infiltration and disease progression.

Main Results:

• Microbial mannose structures on kidney surfaces trigger DC-SIGN-expressing γδ T cells, inducing IL-17a-mediated autoimmune responses.
• Mice with increased kidney mannose structures (Mgat5 deficient) showed enhanced γδ T cell infiltration and spontaneous lupus development.
• N-acetylglucosamine supplementation reduced γδ T cell infiltration and controlled disease progression by promoting tolerogenic N-glycans.

Conclusions:

• A novel mannose-γδ T cell-IL-17a axis in SLE immunopathogenesis has been identified.
• Glycometabolic reprogramming, specifically through N-acetylglucosamine, is a promising therapeutic strategy for autoimmune diseases.
• Targeting glycan structures offers a new avenue for controlling autoimmune disease development and progression.