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ILC2s are tissue-resident cells that produce cytokines IL-5 and IL-13 critical to eosinophilic airway inflammation, mucus production, remodeling, and hyperresponsiveness. Though each ILC subset (ILC1s, ILC2s, ILC3s) is identified by specific transcription factors, cell surface receptors and cytokine profiles, functional plasticity between ILC subtypes occurs in various contexts. IL-18\/IL-18R loci SNPs are linked to asthma in multiple genome-wide association studies and IL-18 has been shown to promote plasticity in ILC2s. Despite this, little is known about the\n                  <jats:italic>in vivo<\/jats:italic>\n                  role of IL-18\/IL-18R on ILC2 responses in the lung. Within hours after mice were exposed to the fungal allergy\n                  <jats:italic>Alternaria alternata<\/jats:italic>\n                  , airway levels of IL-18 and IL-18 receptor expression increased on ST2+ ILCs. Single-cell RNA sequencing of lung cells from Alternaria-challenged mice showed that\n                  <jats:italic>Il18<\/jats:italic>\n                  was largely expressed by alveolar macrophages, while IL-18R was highly expressed in IL-13+ILC2s. Utilizing IL-18 receptor knock-out mice (IL- 18R-\/-), we observed increases in IL-17A production from both ST2+ and ST2-negative ILCs compared to control mice. We further observed an early increase in dual production of IL-5 and IL-17A in ST2+ ILCs followed by enhanced lung eosinophilia in the absence of IL-18R. Together, our findings suggest that IL-18 signaling prevents IL-17A production from ILC2s and subsequent eosinophilia\n                  <jats:italic>in vivo<\/jats:italic>\n                  . A further understanding of the regulation of ILC plasticity may lead to novel therapeutic targets in the treatment of ILC-driven asthma.\n                <\/jats:p>","DOI":"10.1101\/2025.07.17.665289","type":"posted-content","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T16:15:11Z","timestamp":1753114511000},"source":"Crossref","is-referenced-by-count":0,"title":["Activation of IL-17+ ILC subsets in IL-18R-deficient mice during fungal allergen exposure"],"prefix":"10.64898","author":[{"given":"Allyssa N.","family":"Strohm","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blake","family":"Civello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jana H.","family":"Badrani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2240-8715","authenticated-orcid":false,"given":"Lee","family":"Lacasa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kellen","family":"Cavagnero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Portillo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Amadeo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luay H.","family":"Naji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthea","family":"Leng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel E.","family":"Baum","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather M.","family":"McGee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yung-An","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3256-0398","authenticated-orcid":false,"given":"Taylor A.","family":"Doherty","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025072314000722000_2025.07.17.665289v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199010113231505"},{"key":"2025072314000722000_2025.07.17.665289v1.2","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s11882-015-0581-6","article-title":"Insights into Group 2 Innate Lymphoid Cells in Human Airway Disease","volume":"16","year":"2016","journal-title":"Curr Allergy Asthma Rep"},{"key":"2025072314000722000_2025.07.17.665289v1.3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1003988107"},{"key":"2025072314000722000_2025.07.17.665289v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nature08900"},{"key":"2025072314000722000_2025.07.17.665289v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nature08636"},{"key":"2025072314000722000_2025.07.17.665289v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.12.020"},{"key":"2025072314000722000_2025.07.17.665289v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/nature14189"},{"key":"2025072314000722000_2025.07.17.665289v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.07.017"},{"key":"2025072314000722000_2025.07.17.665289v1.9","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1101632"},{"key":"2025072314000722000_2025.07.17.665289v1.10","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00174.2012"},{"key":"2025072314000722000_2025.07.17.665289v1.11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102832"},{"key":"2025072314000722000_2025.07.17.665289v1.12","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.jaci.2018.03.007","article-title":"IL-17-producing ST2(+) group 2 innate lymphoid cells play a pathogenic role in lung inflammation","volume":"143","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"2025072314000722000_2025.07.17.665289v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3443"},{"key":"2025072314000722000_2025.07.17.665289v1.14","doi-asserted-by":"crossref","first-page":"9770","DOI":"10.1038\/s41467-024-54174-5","article-title":"Mechanics-activated fibroblasts promote pulmonary group 2 innate lymphoid cell plasticity propelling silicosis progression","volume":"15","year":"2024","journal-title":"Nat Commun"},{"key":"2025072314000722000_2025.07.17.665289v1.15","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2011.01029.x"},{"key":"2025072314000722000_2025.07.17.665289v1.16","doi-asserted-by":"crossref","unstructured":"Camiolo, M. 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