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Previous studies have demonstrated that the Hla mutant H35A (Hla<jats:sub>H35A<\/jats:sub>) serves as a potent carrier protein for subunit vaccines, yet its immunomodulatory mechanisms remain incompletely understood. Here, we demonstrate that the Hla<jats:sub>H35A<\/jats:sub> fusion enhances vaccine efficacy by targeting A Disintegrin and Metalloproteinase 10 (ADAM10) on dendritic cells (DCs), thereby activating the ADAM10-Notch signaling axis. Using the candidate antigen PA0833 from <jats:italic>Pseudomonas aeruginosa<\/jats:italic> as a model, we show that the Hla<jats:sub>H35A<\/jats:sub>-PA0833 fusion protein (HPF) significantly augments antigen uptake, DC maturation, and Notch-dependent transcriptional programs, particularly in conventional DCs (cDCs). The Hla<jats:sub>H35A<\/jats:sub> fusion drives the differentiation of Notch2-dependent cDC2s, which is marked by ESAM expression and IL-23 secretion. This process promotes Th17 and T follicular helper (Tfh) cell responses in draining lymph nodes, leading to elevated antigen-specific IgG1 titers and robust protection against acute <jats:italic>Pseudomonas aeruginosa<\/jats:italic> lung infection. Notably, ADAM10 or Notch inhibition abrogates these effects. Similarly, human monocyte-derived DCs exhibit enhanced maturation and Notch activation via the Hla<jats:sub>H35A<\/jats:sub>-ADAM10 interaction. Our findings reveal that Hla<jats:sub>H35A<\/jats:sub> is a novel carrier protein that shapes adaptive immunity by modulating cDC2 differentiation via ADAM10-Notch2 signaling, suggesting a promising strategy for Th17\/Tfh-oriented vaccine design.<\/jats:p>","DOI":"10.1038\/s41392-025-02432-3","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:06:33Z","timestamp":1759917993000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Alpha hemolysin enhances the immune response by modulating dendritic cell differentiation via ADAM10-Notch signaling"],"prefix":"10.1038","volume":"10","author":[{"given":"Ke","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Gou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiming","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengmeng","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanda","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengju","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqian","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianjun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenping","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaling","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6971-0786","authenticated-orcid":false,"given":"Quanming","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"2432_CR1","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.3390\/toxins5061140","volume":"5","author":"BJ Berube","year":"2013","unstructured":"Berube, B. 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