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Studies of analogs of a prototypic iNKT cell antigen, \u03b1\u2010galactosylceramide (\u03b1\u2010GalCer), have shown that ceramide structure affects the activities of mouse iNKT cells recognizing the antigen. However, the impact of antigen structure on human iNKT cell activities is less well studied. This study evaluated the antigenicity of eight novel synthetic sulfatide\u2010based lipids with fluorobenzene at the acyl chain terminus and a variety of sphingoid base structures. Using CD1d\u2010tetramers, we evaluated TCR recognition in ex vivo iNKT cells from healthy donors\u2019 peripheral blood mononuclear cells (PBMCs). One analog, SAP\u20103, was commonly recognized by iNKT cells from all donors. SAP\u20103 increased the proportion of CD69\n                    <jats:sup>+<\/jats:sup>\n                    CD25\n                    <jats:sup>+<\/jats:sup>\n                    iNKT cells in a CD1d\u2010dependent manner and triggered IL\u20102 production. Furthermore, SAP\u20103\u2010activated ex vivo iNKT cells increased the frequency of polyfunctional antigen\u2010specific CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells (IFN\u2010\u03b3\n                    <jats:sup>+<\/jats:sup>\n                    IL\u20102\n                    <jats:sup>+<\/jats:sup>\n                    TNF\u2010\u03b1\n                    <jats:sup>+<\/jats:sup>\n                    ) in PBMC stimulation culture. Importantly, repeated in vitro stimulation with SAP\u20103 did not induce iNKT\u2010cell functional anergy, unlike \u03b1\u2010GalCer; instead, SAP\u20103 increased IFN\u2010\u03b3\u2010producing iNKT cells. These findings suggest that the structures of sulfatide analogs critically influence their immunogenicity. SAP\u20103 emerges as a novel human iNKT agonist that enhances antigen\u2010specific CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell responses and represents a promising vaccine and adjuvant candidate.\n                  <\/jats:p>","DOI":"10.1002\/eji.70285","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:39:56Z","timestamp":1790660396000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Sulfatide Analog Recognized by Human iNKT Cells Enhances Polyfunctional Antigen\u2010Specific CD8\n                    <sup>+<\/sup>\n                    T Cell Responses"],"prefix":"10.1002","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5421-1688","authenticated-orcid":false,"given":"Ayaka","family":"Hara","sequence":"first","affiliation":[{"name":"Laboratory of Integrative Cancer Immunology Center for Cancer Research National Cancer Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"DiSapio","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Connecticut  Storrs Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan","family":"Coombs","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Cancer Immunology Center for Cancer Research National Cancer Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9966-4883","authenticated-orcid":false,"given":"Seketoulie","family":"Keretsu","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Cancer Immunology Center for Cancer Research National Cancer Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2624-0366","authenticated-orcid":false,"given":"Svetlana","family":"Korinfskaya","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Cancer Immunology Center for Cancer Research National Cancer Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guzal","family":"Khayrullina","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Cancer Immunology Center for Cancer Research National Cancer Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vibhuti","family":"Joshi","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Cancer Immunology Center for Cancer Research National Cancer Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Masud","family":"Alam","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Cancer Immunology Center for Cancer Research National Cancer Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Cancer Immunology Center for Cancer Research National Cancer Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nargis","family":"Malik","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Cancer Immunology Center for Cancer Research National Cancer Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3350-9818","authenticated-orcid":false,"given":"Emily E.","family":"Steffke","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Cancer Immunology Center for Cancer Research National Cancer Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laila","family":"Latifi","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Cancer Immunology Center for Cancer Research National Cancer Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Hancock","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Cancer Immunology Center for Cancer Research National Cancer Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo D.","family":"Spurgeon","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Cancer Immunology Center for Cancer Research National Cancer Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byram H.","family":"Ozer","sequence":"additional","affiliation":[{"name":"Neuro\u2010Oncology Branch Center For Cancer Research National Cancer Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Gilbert","sequence":"additional","affiliation":[{"name":"Neuro\u2010Oncology Branch Center For Cancer Research National Cancer Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy R.","family":"Howell","sequence":"additional","affiliation":[{"name":"Department of 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