Functional characterization of microbiota-derived MAIT cell agonists in IgA nephropathy

• Grant number: 25/26369-8
• Support Opportunities: Scholarships abroad - Research Internship - Scientific Initiation
• Start date: December 13, 2025
• End date: March 13, 2026
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Lucas Ferreira Mendanha
• Supervisor: Renato Costa Monteiro Filho
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Université Paris Cité, France
• Associated to the scholarship: 24/10027-8 - Migration pattern of MAIT cells between blood circulation and omental adipose tissue associated with changes in intestinal microbiota in the inflammatory context of obesity associated with type 2 diabetes mellitus, BP.IC

Abstract

IgA nephropathy (IgAN) is the most common primary glomerulopathy worldwide and a major cause of chronic kidney disease, driven by the production of undergalactosylated IgA1 (Gd-IgA1), formation of anti-Gd-IgA1 autoantibodies, and mesangial immune complex deposition. Increasing evidence implicates the gut-kidney axis in IgAN pathogenesis, suggesting that dysbiosis and altered mucosal immune responses shape pathogenic IgA production. Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes restricted by the non-polymorphic MR1 molecule and activated by riboflavin-pathway metabolites derived from the microbiota. Beyond their role in antibacterial defense, MAIT cells can promote B-cell maturation and IgA production at mucosal sites. Preliminary data from the GUT-KIDIGAN consortium indicate that MAIT cells are numerically and functionally altered in IgAN, that CARD9-dependent pathways modulate mucosal MAIT and IgA responses, and that pharmacological MAIT blockade reduces Gd-IgA1 levels and mesangial deposition without affecting total IgA. Building on these observations, this project aims to functionally characterize microbiota-derived MAIT-cell agonist ligands and their associated metabolic pathways in the gut microbiota of IgAN patients and IgAN-prone mice, and to relate them to MAIT activation, mucosal IgA production and cytotoxic phenotypes. To this end, we will quantify the relative abundance and functional activity of MAIT agonists from stools and feces using an MR1-dependent MAIT activation bioassay based on WT3-MR1 fibroblasts and murine MAIT cells, in parallel with metagenomic analysis of riboflavin and folate biosynthetic pathways. Bioassay readouts and pathway signatures will be correlated with MAIT activation, mucosal IgA responses and cytotoxic MAIT profiles in blood and kidney. Together, these studies are expected to clarify how IgAN-associated microbiota drive MAIT activation and pathological IgA responses, potentially revealing novel microbiota- and MAIT-targeted therapeutic strategies.