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While current intradermal vaccination regimens confer limited protection outside the context of pediatric extrapulmonary tuberculosis (TB), promising new data indicate that when administered mucosally or intravenously at a higher dose, BCG can induce sterilizing immunity against pulmonary TB in nonhuman primates. BCG is also known to promote nonspecific host resistance against a variety of unrelated infections and is a standard immunotherapy for bladder cancer, suggesting that this innate immune function may contribute to its protective role against TB. Here, we propose that both the mycobacterial-specific and off-target effects of BCG depend on the interplay of adaptive and innate cells and the cytokines they produce, and that the elucidation of this interaction should be a major strategy in the development of more effective BCG-based vaccines and immunotherapies.<\/jats:p>","DOI":"10.1084\/jem.20240496","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T02:20:55Z","timestamp":1740709255000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":13,"title":["Deconvoluting the interplay of innate and adaptive immunity in BCG-induced nonspecific and TB-specific host resistance"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1238-1552","authenticated-orcid":true,"given":"Kerry L.","family":"Hilligan","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02487ts63","id-type":"ROR","asserted-by":"publisher"}],"name":"Malaghan Institute of Medical Research 1 , Wellington,","place":["New Zealand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0035-2802","authenticated-orcid":true,"given":"Patricia A.","family":"Darrah","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}],"name":"Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health 2 , Bethesda, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3133-0849","authenticated-orcid":true,"given":"Robert A.","family":"Seder","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}],"name":"Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health 2 , Bethesda, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7053-2895","authenticated-orcid":true,"given":"Alan","family":"Sher","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}],"name":"National Institute of Allergy and Infectious Diseases, National Institutes of Health 3 Laboratory of Parasitic Diseases, , Bethesda, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2025,3,18]]},"reference":[{"key":"2025081110563728700_bib1","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1093\/infdis\/jiv503","article-title":"Pulmonary but not subcutaneous delivery of BCG vaccine confers protection to tuberculosis-susceptible mice by an interleukin 17-dependent mechanism","volume":"213","author":"Aguilo","year":"2016","journal-title":"J. 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