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Among potential adjuvants, STING-activating cyclic dinucleotides (CDNs) uniquely stimulate a cytosolic sensing pathway activated only by pathogens. Recently, we demonstrated that a CDN-adjuvanted protein subunit vaccine robustly protects against tuberculosis infection in mice. In this study, we delineate the mechanistic basis underlying the efficacy of CDN vaccines for tuberculosis. CDN vaccines elicit CD4 T cells that home to lung parenchyma and penetrate into macrophage lesions in the lung. Although CDNs, like other mucosal vaccines, generate B cell\u2013containing lymphoid structures in the lungs, protection is independent of B cells. Mucosal vaccination with a CDN vaccine induces Th1, Th17, and Th1\u2013Th17 cells, and protection is dependent upon both IL-17 and IFN-\u03b3. Single-cell RNA sequencing experiments reveal that vaccination enhances a metabolic state in Th17 cells reflective of activated effector function and implicate expression of Tnfsf8 (CD153) in vaccine-induced protection. Finally, we demonstrate that simply eliciting Th17 cells via mucosal vaccination with any adjuvant is not sufficient for protection. A vaccine adjuvanted with deacylated monophosphoryl lipid A (MPLA) failed to protect against tuberculosis infection when delivered mucosally, despite eliciting Th17 cells, highlighting the unique promise of CDNs as adjuvants for tuberculosis vaccines.<\/jats:p>","DOI":"10.4049\/jimmunol.2100029","type":"journal-article","created":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T20:21:09Z","timestamp":1640809269000},"page":"407-419","source":"Crossref","is-referenced-by-count":32,"title":["Mucosal Vaccination with Cyclic Dinucleotide Adjuvants Induces Effective T Cell Homing and IL-17\u2013Dependent Protection against <i>Mycobacterium tuberculosis<\/i> Infection"],"prefix":"10.1093","volume":"208","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6289-261X","authenticated-orcid":false,"given":"Robyn M","family":"Jong","sequence":"first","affiliation":[{"name":"Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California , Berkeley, Berkeley, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4773-379X","authenticated-orcid":false,"given":"Erik","family":"Van Dis","sequence":"additional","affiliation":[{"name":"Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California , Berkeley, Berkeley, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel B","family":"Berry","sequence":"additional","affiliation":[{"name":"Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California , Berkeley, Berkeley, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7532-8356","authenticated-orcid":false,"given":"Xammy","family":"Nguyenla","sequence":"additional","affiliation":[{"name":"Division of Infectious Disease and Vaccinology, School of Public Health, University of California , Berkeley, Berkeley, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Baltodano","sequence":"additional","affiliation":[{"name":"Division of Infectious Disease and Vaccinology, School of Public Health, University of California , Berkeley, Berkeley, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5958-7542","authenticated-orcid":false,"given":"Gabrielle","family":"Pastenkos","sequence":"additional","affiliation":[{"name":"Comparative Pathology Laboratory, University of California , Davis, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9610-7627","authenticated-orcid":false,"given":"Chenling","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for Computational Biology, University of California , Berkeley, Berkeley, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9260-4079","authenticated-orcid":false,"given":"Douglas","family":"Fox","sequence":"additional","affiliation":[{"name":"Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California , Berkeley, Berkeley, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nir","family":"Yosef","sequence":"additional","affiliation":[{"name":"Center for Computational Biology, University of California , Berkeley, Berkeley, CA"},{"name":"Department of Electrical Engineering and Computer Sciences, University of California , Berkeley, Berkeley, CA"},{"name":"Ragon Institute of MGH, MIT and Harvard , Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah M","family":"McWhirter","sequence":"additional","affiliation":[{"name":"Aduro Biotech, Inc. , Berkeley, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4182-9048","authenticated-orcid":false,"given":"Sarah A","family":"Stanley","sequence":"additional","affiliation":[{"name":"Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California , Berkeley, Berkeley, CA"},{"name":"Division of Infectious Disease and Vaccinology, School of Public Health, University of California , Berkeley, Berkeley, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,1,15]]},"reference":[{"key":"2025021101004740400_r1","volume-title":"Global Tuberculosis Report 2018.","author":"Geneva: World Health Organization","year":"2018"},{"key":"2025021101004740400_r2","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1001\/jama.1994.03510330076038","article-title":"Efficacy of BCG vaccine in the prevention of tuberculosis. 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