ILC3-guided, metabolite-augmented mucosal “vaccines” for microbiota-specific Treg induction in pre-RA

ILC3s can select microbiota-specific Tregs to establish gut tolerance (Lyu et al., 2022, Nature). Pre-RA may be driven by extra-articular loss of tolerance to the microbiota, with Tregs acting as metabolic sensors (Gao et al., 2025). SCFAs shape Treg biology in disease- and tissue-specific ways (Kim, 2023), and Treg metabolic plasticity is both targetable and disease-relevant (Carbone et al., 2024). This project integrates these threads into a disease-interception strategy: formulate oral or intrarectal microparticles that co-deliver (i) microbiota antigens associated with pre-RA risk, (ii) ILC3-targeting moieties, and (iii) tailored SCFA/metabolic modulators to bias Tregs toward a stable, FOXP3+ suppressive state. Single-cell TCR-seq and metabolomics would track induction and stability of microbiota-specific Tregs and their metabolic signatures over time. Unlike generic probiotic/SCFA supplementation, this approach targets the antigen-selection node (ILC3) while tuning Treg metabolism, aiming for durable, antigen-specific tolerance that could prevent RA onset.

References:

1. Restoring immune tolerance in pre-RA: immunometabolic dialogue between gut microbiota and regulatory T cells. Anqi Gao, R. Wu, Yanfei Mu, Ruqing Jin, Saixin Jiang, Chong Gao, Xiaofeng Li, Caihong Wang (2025). Frontiers in Immunology.
2. Metabolic Plasticity of Regulatory T Cells in Health and Autoimmunity.. F. Carbone, Alessandra Colamatteo, Claudia La Rocca, M. Lepore, Claudia Russo, Giusy De Rosa, Alessandro Matarese, C. Procaccini, G. Matarese (2024). Journal of Immunology.
3. Complex regulatory effects of gut microbial short-chain fatty acids on immune tolerance and autoimmunity. Chang H. Kim (2023). Cellular & Molecular Immunology.
4. ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut. Mengze Lyu, Hiroaki Suzuki, Lan Kang, Fabrina Gaspal, Wen-Tao Zhou, J. Goc, Lei Zhou, Jordan Zhou, Wen Zhang, Zeli Shen, J. Fox, R. Sockolow, T. Laufer, Yong Fan, G. Eberl, D. Withers, Gregory F. Sonnenberg (2022). Nature.