Commensal-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 identified trehalose monocorynomycolate (TMCM) from Corynebacterium mastitidis as a potent stimulator of interleukin 17 (IL-17) production by Vγ4 γδ T cells at the ocular surface. Mechanistically, TMCM-induced IL-17 responses depended on IL-1R and γδ T cell receptor (TCR) signaling, with TCR engagement further enhancing IL-1R1 expression on γδ T cells. Synthetic TMCM alone recapitulated the effect of Corynebacterium mastitidis in eliciting protective γδ T cell immunity at the ocular surface to prevent bacterial infection. Moreover, TMCM also promoted protective immunity in downstream eye-draining tissues and skin. These findings establish TMCM as a broadly applicable mediator of commensal-driven immune defense and highlight its therapeutic potential to strengthen IL-17-mediated protection at barrier sites.