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Developing a vaccine is crucial to complement current control measures, which necessitates a thorough understanding of host immune responses. By leveraging controlled human infection models and high-dimensional immunophenotyping, here we investigated the immune remodeling following infection with 50\u2009<jats:italic>Necator americanus<\/jats:italic> L3 hookworm larvae in four na\u00efve volunteers over two years of follow-up and compared the profiles with naturally infected populations in endemic areas. Increased plasmacytoid dendritic cell frequency and diminished responsiveness to Toll-like receptor 7\/8 ligand were observed in both controlled and natural infection settings. Despite the increased CD45RA<jats:sup>+<\/jats:sup> regulatory T cell (T<jats:sub>regs<\/jats:sub>) frequencies in both settings, markers of T<jats:sub>regs<\/jats:sub> function, including inducible T-cell costimulatory (ICOS), tumor necrosis factor receptor 2 (TNFR2), and latency-associated peptide (LAP), as well as in vitro T<jats:sub>regs<\/jats:sub> suppressive capacity were higher in natural infections. Taken together, this study provides unique insights into the immunological trajectories following a first-in-life hookworm infection compared to natural infections.<\/jats:p>","DOI":"10.1038\/s41467-024-50313-0","type":"journal-article","created":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T04:01:51Z","timestamp":1721102511000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Controlled human hookworm infection remodels plasmacytoid dendritic cells and regulatory T cells towards profiles seen in natural infections in endemic areas"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2728-1829","authenticated-orcid":false,"given":"Mikhael D.","family":"Manurung","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friederike","family":"Sonnet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3088-3380","authenticated-orcid":false,"given":"Marie-Astrid","family":"Hoogerwerf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline J.","family":"Janse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne","family":"Kruize","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura de","family":"Bes-Roeleveld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9892-218X","authenticated-orcid":false,"given":"Marion","family":"K\u00f6nig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Loukas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1497-0799","authenticated-orcid":false,"given":"Benjamin G.","family":"Dewals","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taniawati","family":"Supali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4835-1032","authenticated-orcid":false,"given":"Simon P.","family":"Jochems","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5052-2830","authenticated-orcid":false,"given":"Meta","family":"Roestenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1387-7229","authenticated-orcid":false,"given":"Mariateresa","family":"Coppola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7666-1441","authenticated-orcid":false,"given":"Maria","family":"Yazdanbakhsh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,16]]},"reference":[{"key":"50313_CR1","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1016\/j.ijpara.2021.11.001","volume":"51","author":"A Loukas","year":"2021","unstructured":"Loukas, A., Maizels, R. 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