Commensal-derived Trehalose Monocorynomycolate Triggers γδ T Cell-driven Protective Ocular Barrier Immunity

SUMMARY Commensals shape host physiology through molecular crosstalk with host receptors. Identifying specific microbial factors that causally influence host immunity is key to understanding homeostasis at the host-microbe interface and advancing microbial-based therapeutics. Here, we identify trehalose monocorynomycolate (TMCM) from Corynebacterium mastitidis (C. mast) as a potent stimulator of IL-17 production by γδ T cells at the ocular surface. Mechanistically, TMCM-driven IL-17 responses require both IL-1 signals and γδ TCR signaling, which also supports endogenous γδ T cell IL-1R1 expression. Notably, synthetic TMCM alone is sufficient to mimic the effect of C. mast in inducing γδ T cell immunity and protect against pathogenic corneal infection. Our findings establish TMCM as a key mediator of commensal-driven immune defense, highlighting its potential as a γδ T cell adjuvant and a microbiome-informed therapeutic to enhance IL-17-driven protection at barrier sites such as the ocular surface. HIGHLIGHTS Corynomycolates enable ocular C. mast colonization and protective IL-17 immunity TMCM drives IL-17 from γδ T cells through TCR and IL-1R signaling γδ TCR signaling maintains the expression of endogenous IL-1R1 Synthetic TMCM mimics the ability of C. mast to induce γδ T cell immunity in the eye TMCM protects against P. aeruginosa keratitis, highlighting its therapeutic potential Competing Interest Statement RRC, XX and BS: patent application "CORYNEBACTERIUM MASTITIDIS-DERIVED MYCOLATES FOR TREATING OCULAR SURFACE DISEASES" No. 63/642,512 filed May 3, 2024. HHS Reference: E‑126-2024-0-US-01