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

Xu, X.; Rigas, Y. E.; Mattapallil, M. J.; Guo, J.; Nagarajan, V.; Bohrnsen, E.; Richards, C.; Gupta, A.; Gaud, G.; Love, P. E.; Jiang, T.; Zhang, A.; Xu, B.; Peng, Z.; Jittayasothorn, Y.; Carr, M.; Magone, M. T.; Brandes, N. T.; Shane, J.; Schwarz, B.; St. Leger, A. J.; Caspi, R.

doi:10.1101/2025.03.17.643820

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bioRxiv · 10.1101/2025.03.17.643820

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

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Abstract

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 {gamma}{delta} T cells at the ocular surface. Mechanistically, TMCM-driven IL-17 responses require both IL-1 signals and {gamma}{delta} TCR signaling, which also supports endogenous {gamma}{delta} T cell IL-1R1 expression. Notably, synthetic TMCM alone is sufficient to mimic the effect of C. mast in inducing {gamma}{delta} 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 {gamma}{delta} T cell adjuvant and a microbiome-informed therapeutic to enhance IL-17-driven protection at barrier sites such as the ocular surface. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/643820v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@63139forg.highwire.dtl.DTLVardef@9d6978org.highwire.dtl.DTLVardef@775e37org.highwire.dtl.DTLVardef@ca84b6_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LICorynomycolates enable ocular C. mast colonization and protective IL-17 immunity C_LIO_LITMCM drives IL-17 from {gamma}{delta} T cells through TCR and IL-1R signaling C_LIO_LI{gamma}{delta} TCR signaling maintains the expression of endogenous IL-1R1 C_LIO_LISynthetic TMCM mimics the ability of C. mast to induce {gamma}{delta} T cell immunity in the eye C_LIO_LITMCM protects against P. aeruginosa keratitis, highlighting its therapeutic potential C_LI

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Xu, X., Rigas, Y. E., Mattapallil, M. J., Guo, J., Nagarajan, V., Bohrnsen, E., Richards, C., Gupta, A., Gaud, G., Love, P. E., Jiang, T., Zhang, A., Xu, B., Peng, Z., Jittayasothorn, Y., Carr, M., Magone, M. T., Brandes, N. T., Shane, J., Schwarz, B., St. Leger, A. J., Caspi, R.. 2025-03-18. Commensal-derived Trehalose Monocorynomycolate Triggers γδ T Cell-driven Protective Ocular Barrier Immunity. https://doi.org/10.1101/2025.03.17.643820

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