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We previously demonstrated that changing the BCG route and dose from 5 \u00d7 105 CFUs ID to 5 \u00d7 107 CFUs i.v. resulted in prevention of Mycobacterium tuberculosis (Mtb) infection and TB disease in highly susceptible nonhuman primates. Identifying immune mechanisms protection following i.v. BCG will facilitate development of more effective vaccines against TB. Here, we depleted lymphocyte subsets prior to and during Mtb challenge in i.v. BCG\u2013vaccinated macaques to identify those necessary for protection. Depletion of adaptive CD4 T cells, but not adaptive CD8\u03b1\u03b2 T cells, resulted in loss of protection with increased Mtb burdens and dissemination, indicating that CD4 T cells are critical to i.v. BCG\u2013mediated protection. Depletion of unconventional CD8\u03b1-expressing lymphocytes (NK cells, innate T cells, and CD4+CD8\u03b1+ double-positive T cells) abrogated protection in most i.v. BCG\u2013immunized macaques, supporting further investigation into which of these cell subsets contribute to protection after vaccination.<\/jats:p>","DOI":"10.1084\/jem.20241571","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T10:04:08Z","timestamp":1738836248000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":49,"title":["Intravenous BCG-mediated protection against tuberculosis requires CD4+ T cells and CD8\u03b1+ lymphocytes"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4789-3873","authenticated-orcid":true,"given":"Andrew W.","family":"Simonson","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04zvr0529","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Pittsburgh School of Medicine 1 Department of Microbiology and Molecular Genetics, , Pittsburgh, PA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/04zvr0529","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Vaccine Research, University of Pittsburgh School of Medicine 2 , Pittsburgh, PA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1136-4793","authenticated-orcid":true,"given":"Joseph J.","family":"Zeppa","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04zvr0529","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Pittsburgh School of Medicine 1 Department of Microbiology and Molecular Genetics, , Pittsburgh, PA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/04zvr0529","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Vaccine Research, University of Pittsburgh School of Medicine 2 , Pittsburgh, PA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0568-1701","authenticated-orcid":true,"given":"Allison N.","family":"Bucsan","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 (NIAID), National Institutes of Health (NIH) 3 , Bethesda, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3158-7337","authenticated-orcid":true,"given":"Michael C.","family":"Chao","sequence":"additional","affiliation":[{"name":"Ragon Institute of MGH, MIT, and Harvard 4 , Cambridge, MA,","place":["USA"]},{"name":"Harvard T.H. 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