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Human TOLLIP deficiency, regulated by single-nucleotide polymorphism rs5743854, is associated with increased tuberculosis risk and diminished frequency of bacillus Calmette\u2013Gu\u00e9rin vaccine-specific CD4+ T cells in infants. How TOLLIP influences adaptive immune responses remains poorly understood. To understand the mechanistic relationship between TOLLIP and adaptive immune responses, we used human genetic and murine models to evaluate the role of TOLLIP in dendritic cell (DC) function. In healthy volunteers, TOLLIP single-nucleotide polymorphism rs5743854 G allele was associated with decreased TOLLIP mRNA and protein expression in DCs, along with LPS-induced IL-12 secretion in peripheral blood DCs. As in human cells, LPS-stimulated Tollip\u2212\/\u2212 bone marrow\u2013derived murine DCs secreted less IL-12 and expressed less CD40. Tollip was required in lung and lymph node\u2013resident DCs for optimal induction of MHC class II and CD40 expression during the first 28 d of Mycobacterium tuberculosis infection in mixed bone marrow chimeric mice. Tollip\u2212\/\u2212 mice developed fewer M. tuberculosis\u2013specific CD4+ T cells after 28 d of infection and diminished responses to bacillus Calmette\u2013Gu\u00e9rin vaccination. Furthermore, Tollip\u2212\/\u2212 DCs were unable to optimally induce T cell proliferation. Taken together, these data support a model where TOLLIP-deficient DCs undergo suboptimal maturation after M. tuberculosis infection, impairing T cell activation and contributing to tuberculosis susceptibility.<\/jats:p>","DOI":"10.4049\/jimmunol.2200030","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T15:14:20Z","timestamp":1657811660000},"page":"435-445","source":"Crossref","is-referenced-by-count":7,"title":["TOLLIP Optimizes Dendritic Cell Maturation to Lipopolysaccharide and <i>Mycobacterium tuberculosis<\/i>"],"prefix":"10.1093","volume":"209","author":[{"given":"Sambasivan","family":"Venkatasubramanian","sequence":"first","affiliation":[{"name":"University of Washington , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn","family":"Pryor","sequence":"additional","affiliation":[{"name":"University of Washington , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7142-4394","authenticated-orcid":false,"given":"Courtney","family":"Plumlee","sequence":"additional","affiliation":[{"name":"Seattle Children\u2019s Research Institute , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7850-3498","authenticated-orcid":false,"given":"Sarah B","family":"Cohen","sequence":"additional","affiliation":[{"name":"Seattle Children\u2019s Research Institute , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7669-2803","authenticated-orcid":false,"given":"Jason D","family":"Simmons","sequence":"additional","affiliation":[{"name":"University of Washington , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander J","family":"Warr","sequence":"additional","affiliation":[{"name":"University of Washington , Seattle, WA"},{"name":"Baylor School of Medicine , Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D","family":"Graustein","sequence":"additional","affiliation":[{"name":"University of Washington , Seattle, WA"},{"name":"VA Puget Sound Healthcare System , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5014-6687","authenticated-orcid":false,"given":"Aparajita","family":"Saha","sequence":"additional","affiliation":[{"name":"University of Washington , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas R","family":"Hawn","sequence":"additional","affiliation":[{"name":"University of Washington , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin B","family":"Urdahl","sequence":"additional","affiliation":[{"name":"Seattle Children\u2019s Research Institute , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2997-7988","authenticated-orcid":false,"given":"Javeed A","family":"Shah","sequence":"additional","affiliation":[{"name":"University of Washington , Seattle, WA"},{"name":"VA Puget Sound Healthcare System , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,8,1]]},"reference":[{"key":"2025021008235856400_r1","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1164\/rccm.201611-2346OC","article-title":"A functional Toll-interacting protein variant is associated with bacillus Calmette-Gu\u00e9rin\u2013specific immune responses and tuberculosis","volume":"196","author":"Shah","year":"2017","journal-title":"Am. 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