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Efforts to control TB are hampered by the lengthy and cumbersome treatment required to eradicate the <jats:italic>Mtb<\/jats:italic> infection. Bacterial persistence during exposure to bactericidal antibiotics is at least partially mediated by the bacterial stringent response enzyme, Rel<jats:sub>Mtb<\/jats:sub>. A therapeutic DNA vaccine targeting Rel<jats:sub>Mtb<\/jats:sub> has been shown to increase the efficacy of antitubercular drugs, and fusing macrophage-inflammatory protein 3\u03b1 (MIP-3\u03b1), which interacts with CCR6 on immature dendritic cells (iDCs), to Rel<jats:sub>Mtb<\/jats:sub> further increases the vaccine\u2019s therapeutic efficacy. A secondary analysis of these prior studies elucidated prominent sex-based differences in vaccine therapeutic efficacy, with female mice showing improved microbial outcomes compared to males as a result of the Rel and MIP-3\u03b1-Rel vaccine constructs, with a more pronounced sex-associated difference in the MIP-3\u03b1-Rel group. In the current study, we addressed the hypothesis that these sex-related differences are at least in part due to differential DC activation\/function soon after vaccination. An E\u03b1GFP reporter vaccine model was used to track vaccine antigen presentation in the draining node with flow cytometry panels by an antibody Y-Ae which binds the E\u03b1 peptide tag in complex with I-A<jats:sup>b<\/jats:sup> MHC-II molecules. Additionally, a qRT-PCR panel assessing DC-related genes compared sexes receiving the MIP-3\u03b1-Rel vaccine. MIP-3\u03b1-E\u03b1GFP groups had more DCs presenting vaccine antigen infiltrating from the periphery, with more abundant Langerhans cells in males and greater CD8+ CD103+ cross-presenting dermal DCs in females. This model also shows there is greater DC activation, as measured by CD80 and MHC II MFI, by MIP-3\u03b1 compared to E\u03b1GFP alone, especially in female mice. The genetic panel showed females more enriched for chemokines and genes related to cell movement and cross-presentation. Our findings are consistent with the sex- and MIP-3\u03b1-related differences seen in the therapeutic model and supports the hypothesis that in both sexes MIP-3\u03b1 enhances vaccine uptake and cell activation by peripheral iDCs. Additionally, female mice showed greater levels of antigen presentation, especially in DCs able to cross-present antigen, likely explaining why they had the best outcomes. Further studies are required to understand underlying mechanisms and to link APC results directly to T-cell responses.<\/jats:p>","DOI":"10.1038\/s41598-025-06532-6","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T21:14:07Z","timestamp":1751404447000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["MIP-3\u03b1-antigen fusion DNA vaccine enhances sex differences in tuberculosis model and alters dendritic cell activity early post vaccination"],"prefix":"10.1038","volume":"15","author":[{"given":"James T.","family":"Gordy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rowan E.","family":"Bates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Glass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Meza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangchen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Schill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alannah D.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengyixin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaleel","family":"Plunkett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Styliani","family":"Karanika","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petros C.","family":"Karakousis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard B.","family":"Markham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"6532_CR1","unstructured":"WHO tuberculosis. 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