biostudies-literatureUnknownXu XIntramural NIH HHSNEI NIH HHSCommensals 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 <i>Corynebacterium mastitidis</i> (<i>C. mast</i>) 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 <i>C. mast</i> in inducing γδ T cell immunity and protect against pathogenic corneal infection. Our findings establish TMbioRxiv : the preprint server for biology2025.03.17.643820https://www.ebi.ac.uk/biostudies/studies/S-EPMC11956969biostudies-literatureCommensal-derived Trehalose Monocorynomycolate Triggers γδ T Cell-driven Protective Ocular Barrier Immunity.PMC11956969U24 EY035102P30 EY008098T32 EY017271Z01 EY000184R01 EY032482Brandes NTGaud GSchwarz BCarr MShane JMattapallil MJJiang TPeng ZRichards CGupta ACaspi RRLove PEGuo JJittayasothorn YXu BRigas YEMagone MTXu XNagarajan VSt Leger AJZhang ABohrnsen EfalseCommensal-derived Trehalose Monocorynomycolate Triggers γδ T Cell-driven Protective Ocular Barrier Immunity.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 <i>Corynebacterium mastitidis</i> (<i>C. mast</i>) 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 <i>C. mast</i> in inducing γδ T cell immunity and protect against pathogenic corneal infection. Our findings establish TM2025-01-01T00:00:00Z2025 Mar2026-04-14T03:24:34.677Z2025-07-05T03:04:33.783ZS-EPMC119569694016622310.1101/2025.03.17.643820