MAIT cells drive chronic inflammation in a genetically diverse murine model of spontaneous colitis.

Loh, L.; Orlicky, D.; Spengler, A.; Levens, C.; Celli, S.; Domenico, J.; Klarquist, J.; Onyiah, J.; Matsuda, J.; Kuhn, K. A.; Gapin, L.

doi:10.1101/2023.11.29.569225

bioRxiv · 10.1101/2023.11.29.569225

MAIT cells drive chronic inflammation in a genetically diverse murine model of spontaneous colitis.

Loh, L.·Orlicky, D.·Spengler, A.·Levens, C.·Celli, S.·Domenico, J.·Klarquist, J.·Onyiah, J.·Matsuda, J.·Kuhn, K. A.·Gapin, L.

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Abstract

Background & aimsLymphocytes that produce IL-17 can confer protective immunity during infections by pathogens, yet their involvement in inflammatory diseases is a subject of debate. Although these cells may perpetuate inflammation, resulting in tissue damage, they are also capable of contributing directly or indirectly to tissue repair, thus necessitating more detailed investigation. Mucosal-Associated-Invariant-T (MAIT) cells are innate-like T cells, acquiring a type III phenotype in the thymus. Here, we dissected the role of MAIT cells in vivo using a spontaneous colitis model in a genetically diverse mouse strain. MethodsMultiparameter spectral flow cytometry and scRNAseq were used to characterize MAIT and immune cell dynamics and transcriptomic signatures respectively, in the collaborative-cross strain, CC011/Unc and CC011/Unc-Traj33-/-. ResultsIn contrast to many conventional mouse laboratory strains, the CC011 strain harbors a high baseline population of MAIT cells. We observed an age-related increase in colonic MAIT cells, Th17 cells, regulatory T cells, and neutrophils, which paralleled the development of spontaneous colitis. This progression manifested histological traits reminiscent of human IBD. The transcriptomic analysis of colonic MAIT cells from CC011 revealed an activation profile consistent with an inflammatory milieu, marked by an enhanced type-III response. Notably, IL-17A was abundantly secreted by MAIT cells in the colons of afflicted mice. Conversely, in the MAIT cell-deficient CC011-Traj33-/- mice, there was a notable absence of significant colonic histopathology. Furthermore, myeloperoxidase staining indicated a substantial decrease in colonic neutrophils. ConclusionsOur findings suggest that MAIT cells play a pivotal role in modulating the severity of intestinal pathology, potentially orchestrating the inflammatory process by driving the accumulation of neutrophils within the colonic environment.

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Loh, L., Orlicky, D., Spengler, A., Levens, C., Celli, S., Domenico, J., Klarquist, J., Onyiah, J., Matsuda, J., Kuhn, K. A., Gapin, L.. 2023-12-01. MAIT cells drive chronic inflammation in a genetically diverse murine model of spontaneous colitis.. https://doi.org/10.1101/2023.11.29.569225

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