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CD11b, the \u03b1 subunit of integrin CR3 (CD11b\/CD18, \u03b1<jats:sub>M<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub>), is essential for mice to fight against systemic <jats:italic>Candida albicans<\/jats:italic> infections. Live elongating <jats:italic>C. albicans<\/jats:italic> activates CR3 in immune cells. However, the hyphal ligands that activate CR3 are not well defined. Here, we discovered that the <jats:italic>C. albicans<\/jats:italic> Als family proteins are recognized by the I domain of CD11b in macrophages. This recognition synergizes with the \u03b2-glucan-bound lectin-like domain to activate CR3, thereby promoting Syk signaling and inflammasome activation. Dectin-2 activation serves as the \u201coutside-in signaling\u201d for CR3 activation at the entry site of incompletely sealed phagosomes, where a thick cuff of F-actin forms to strengthen the local interaction. In vitro, CD18 partially contributes to IL-1\u03b2 release from dendritic cells induced by purified hyphal Als3. In vivo, Als3 is vital for <jats:italic>C. albicans<\/jats:italic> clearance in mouse kidneys. These findings uncover a novel family of ligands for the CR3 I domain that promotes fungal clearance.<\/jats:p>","DOI":"10.1038\/s41467-024-48093-8","type":"journal-article","created":{"date-parts":[[2024,5,9]],"date-time":"2024-05-09T19:02:21Z","timestamp":1715281341000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Hyphal Als proteins act as CR3 ligands to promote immune responses against Candida albicans"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0336-0410","authenticated-orcid":false,"given":"Tingting","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norma V.","family":"Solis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9381-780X","authenticated-orcid":false,"given":"Michaela","family":"Marshall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Garleb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengli","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Pearlman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7278-3700","authenticated-orcid":false,"given":"Scott G.","family":"Filler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3489-7103","authenticated-orcid":false,"given":"Haoping","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,9]]},"reference":[{"key":"48093_CR1","doi-asserted-by":"publisher","first-page":"18026","DOI":"10.1038\/nrdp.2018.26","volume":"4","author":"PG Pappas","year":"2018","unstructured":"Pappas, P. 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