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IL-17R signaling is essential to prevent OPC in mice and humans, but the individual roles of its ligands, IL-17A, IL-17F, and IL-17AF, are less clear. A homozygous IL-17F deficiency in mice does not cause OPC susceptibility, whereas mice lacking IL-17A are moderately susceptible. In humans, a rare heterozygous mutation in IL-17F (IL-17F.S65L) was identified that causes chronic mucocutaneous candidiasis, suggesting the existence of essential antifungal pathways mediated by IL-17F and\/or IL-17AF. To investigate the role of IL-17F and IL-17AF in more detail, we exploited this \u201cexperiment of nature\u201d by creating a mouse line bearing the homologous mutation in IL-17F (Ser65Leu) by CRISPR\/Cas9. Unlike Il17f\u2212\/\u2212 mice that are resistant to OPC, Il17fS65L\/S65L mice showed increased oral fungal burdens similar to Il17a\u2212\/\u2212 mice. In contrast to humans, however, disease was only evident in homozygous, not heterozygous, mutant mice. The mutation was linked to modestly impaired CXC chemokine expression and neutrophil recruitment to the infected tongue but not to alterations in oral antimicrobial peptide expression. These findings suggest mechanisms by which the enigmatic cytokine IL-17F contributes to host defense against fungi. Moreover, because these mice do not phenocopy Il17f\u2212\/\u2212 mice, they may provide a valuable tool to interrogate IL-17F and IL-17AF function in vivo in other settings.<\/jats:p>","DOI":"10.4049\/jimmunol.2000394","type":"journal-article","created":{"date-parts":[[2020,6,29]],"date-time":"2020-06-29T16:45:13Z","timestamp":1593449113000},"page":"720-730","source":"Crossref","is-referenced-by-count":13,"title":["An IL-17F.S65L Knock-In Mouse Reveals Similarities and Differences in IL-17F Function in Oral Candidiasis: A New Tool to Understand IL-17F"],"prefix":"10.1093","volume":"205","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9721-7948","authenticated-orcid":false,"given":"Chunsheng","family":"Zhou","sequence":"first","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, University of Pittsburgh , Pittsburgh, PA 15261"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4951-8105","authenticated-orcid":false,"given":"Leticia","family":"Monin","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, University of Pittsburgh , Pittsburgh, PA 15261"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6598-0546","authenticated-orcid":false,"given":"Rachael","family":"Gordon","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Pittsburgh , Pittsburgh, PA 15261"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0327-0095","authenticated-orcid":false,"given":"Felix E Y","family":"Aggor","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, University of Pittsburgh , Pittsburgh, PA 15261"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1611-0242","authenticated-orcid":false,"given":"Rami","family":"Bechara","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, University of Pittsburgh , Pittsburgh, PA 15261"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tara N","family":"Edwards","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Pittsburgh , Pittsburgh, PA 15261"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0598-0047","authenticated-orcid":false,"given":"Daniel H","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Pittsburgh , Pittsburgh, PA 15261"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2607-8642","authenticated-orcid":false,"given":"Sebastien","family":"Gingras","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Pittsburgh , Pittsburgh, PA 15261"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8511-2041","authenticated-orcid":false,"given":"Sarah L","family":"Gaffen","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, University of Pittsburgh , Pittsburgh, PA 15261"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,8,1]]},"reference":[{"key":"2025030417504415600_r1","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3004404","article-title":"Hidden killers: human fungal infections","volume":"4","author":"Brown","year":"2012","journal-title":"Sci. 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