Lung CD4+ resident memory T cells use airway secretory cells to stimulate and regulate neutrophilic allergic airways disease.

Ravi, V. R.; Korkmaz, F. T.; Lyon De Ana, C.; Lu, L.; Shao, F.-Z.; Odom, C. V.; Barker, K. A.; Ramanujan, A.; Niszczak, E. N.; Goltry, W. N.; Martin, I. M. C.; Ha, C. T.; Quinton, L. J.; Jones, M. R.; Fine, A.; Welch, J. D.; Chen, F.; Belkina, A. C.; Mizgerd, J. P.; Shenoy, A. T.

doi:10.1101/2024.10.03.616494

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bioRxiv · 10.1101/2024.10.03.616494

Lung CD4+ resident memory T cells use airway secretory cells to stimulate and regulate neutrophilic allergic airways disease.

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Abstract

Neutrophilic asthma is a vexing disease, but mechanistic and therapeutic advancement will require better models of allergy-induced airway neutrophilia. Here, we find that periodic ovalbumin (OVA) inhalation in sensitized mice elicits allergic airway inflammation and pathophysiology mimicking neutrophilic asthma. OVA-experienced murine lungs harbor diverse clusters of CD4+ resident memory TRM cells, including unconventional ROR{gamma}tnegative/low TH17 cells. Acute OVA challenge instigates IL-17A secretion from these TRM cells, driving CXCL5 production from Muc5achigh airway secretory cells, leading to destructive airway neutrophilia. The TRM- and epithelial-cell signals discovered herein are also observed in adult human asthmatic airways. Epithelial antigen presentation regulates this biology by skewing TRM cells towards TH2 and TH1 fates, so that the TH1-related IFN-{gamma} suppresses IL-17A-driven, CXCL5-mediated airway neutrophilia. Concordantly, in vivo IFN-{gamma} supplementation improves disease outcomes. Thus, using our model of neutrophilic asthma we identify lung epithelial-CD4+ TRM cell crosstalk as a key rheostat of allergic airway neutrophilia. HighlightsO_LIRecurrent OVA inhalation experience predisposes mice to allergic airways neutrophilia C_LIO_LINeutrophil-prone lungs harbor CD4+ TRM cells including ROR{gamma}tnegative/low TH17 cells C_LIO_LIMuc5achigh secretory cells instruct CD4+ TRM fates and neutrophilia via MHC-II and CXCL5, respectively C_LIO_LIProphylactic or therapeutic delivery of IFN-{gamma} curbs allergic airway neutrophilia C_LI

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Ravi, V. R., Korkmaz, F. T., Lyon De Ana, C., Lu, L., Shao, F.-Z., Odom, C. V., Barker, K. A., Ramanujan, A., Niszczak, E. N., Goltry, W. N., Martin, I. M. C., Ha, C. T., Quinton, L. J., Jones, M. R., Fine, A., Welch, J. D., Chen, F., Belkina, A. C., Mizgerd, J. P., Shenoy, A. T.. 2024-10-04. Lung CD4+ resident memory T cells use airway secretory cells to stimulate and regulate neutrophilic allergic airways disease.. https://doi.org/10.1101/2024.10.03.616494

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