Food Allergen Challenge Elicits Gut-Derived, Migratory iILC2s that Reshape the Immune Profile of Remote Lungs 2309438

Abstract Introduction Allergic progression across the skin-gut-lung axis remains unclear. A subset of migratory, intestine-derived inflammatory type 2 innate lymphoid cells (iILC2s) expand in response to IL-25 and disseminate type 2 immunity along the gut-lung axis (GLA) in helminth infection. Here we tested if food allergen challenge similarly elicits mucosal organ crosstalk by expanding gut-derived, lung-migratory iILC2s, promoting lung IL-13-mediated mucin dysregulation. Methods Wildtype mice sensitized by intraperitoneal (i.p.) injections of ovalbumin (OVA)+alum or PBS+alum (days 0, 14) were challenged by oral gavage (o.g.) with OVA or PBS on days 21-23. Sphingosine-1 phosphate (S1P) modulator FTY720 blocked intestinal egress of iILC2s. Lung, small intestine, and mesenteric lymph nodes (MLNs) were analyzed by RT-PCR and flow cytometry. IL-25 (i.p.) induced lung-migratory iILC2s in an allergen-free system. DdblGATA1-/- (eosinophil deficient) mice were used to parse effects of iILC2s and eosinophils. Results iILC2s (CD45+Lin-CD4-ST2-KLRG1hiIL17Rb1+IL7Ra+) were found in the lung within 1 hour of OVA o.g. challenge. Lung iILC2s positively correlated with Il13 mRNA levels (R2=0.77, p = 0.02), and preceded eosinophil infiltration and mucin dysregulation. O.g. challenge increased duodenal tuft cell signatures (p < 0.05) and IL-25 protein (p < 0.00005), correlating with local iILC2 expansion (R2=0.68, p < 0.0005). FTY720 inhibition of iILC2 intestinal egress reduced iILC2 numbers in MLNs and lungs, indicating intestinal origin of lung-migrated iILC2s. IL-25 treatment (bypassing allergen) elicited gut-derived, lung-migratory iILC2s that correlated with lung Il13 (R2=0.84, p < 0.0005) and preceded eosinophil infiltration and induction of Muc5ac mucins. IL-25 likewise elicited lung-migrated iILC2s and an Il13 signature in eosinophil deficient mice; however, Muc5ac was not increased in the absence of eosinophils. Conclusion Our data implicate migratory iILC2s in food allergen-driven dissemination of type 2 immunity along the GLA. Funding Source This work was supported by NIH R01AI168134 to Lisa A. Spencer. Topic Categories Mucosal and Regional Immunology (MUC)