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Two major subpopulations of human iNKT cells have been delineated, a CD4\n                    <jats:sup>\u2212<\/jats:sup>\n                    subset that has a T\n                    <jats:sub>H1<\/jats:sub>\n                    \/cytolytic profile, and a CD4\n                    <jats:sup>+<\/jats:sup>\n                    subset that appears polyfunctional and can produce both regulatory and immunostimulatory cytokines. Whether these two subsets differ in anti\u2010tumour effects is not known. Using live cell imaging, we found that CD4\n                    <jats:sup>\u2212<\/jats:sup>\n                    iNKT cells limited growth of CD1d\n                    <jats:sup>+<\/jats:sup>\n                    Epstein\u2013Barr virus (EBV)\u2010infected B\u2010lymphoblastoid spheroids in vitro, whereas CD4\n                    <jats:sup>+<\/jats:sup>\n                    iNKT cells showed little or no direct anti\u2010tumour activity. However, the effects of the two subsets were reversed when we tested them as adoptive immunotherapies in vivo using a xenograft model of EBV\u2010driven human B cell lymphoma. We found that EBV\u2010infected B cells down\u2010regulated CD1d in vivo, and administering CD4\n                    <jats:sup>\u2212<\/jats:sup>\n                    iNKT cells had no discernable impact on tumour mass. In contrast, xenotransplanted mice bearing lymphomas showed rapid reduction in tumour mass after administering CD4\n                    <jats:sup>+<\/jats:sup>\n                    iNKT cells. Immunotherapeutic CD4\n                    <jats:sup>+<\/jats:sup>\n                    iNKT cells trafficked to both spleen and tumour and were associated with subsequently enhanced responses of xenotransplanted human T cells against EBV. CD4\n                    <jats:sup>+<\/jats:sup>\n                    iNKT cells also had adjuvant\u2010like effects on monocyte\u2010derived DCs and promoted antigen\u2010dependent responses of human T cells in vitro. These results show that allogeneic CD4\n                    <jats:sup>+<\/jats:sup>\n                    iNKT cellular immunotherapy leads to marked anti\u2010tumour activity through indirect pathways that do not require tumour cell CD1d expression and that are associated with enhanced activity of antigen\u2010specific T cells.\n                  <\/jats:p>","DOI":"10.1111\/imm.13799","type":"journal-article","created":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T03:00:18Z","timestamp":1715569218000},"page":"627-640","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Human\n                    <scp>CD4<\/scp>\n                    <sup>+<\/sup>\n                    <scp>iNKT<\/scp>\n                    cell adoptive immunotherapy induces anti\u2010tumour responses against\n                    <scp>CD1d<\/scp>\n                    \u2010negative\n                    <scp>EBV<\/scp>\n                    \u2010driven B lymphoma"],"prefix":"10.1111","volume":"172","author":[{"given":"Dana C.","family":"Baiu","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Immunology University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akshat","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L.","family":"Schehr","sequence":"additional","affiliation":[{"name":"Carbone Comprehensive Cancer Center University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayati","family":"Basu","sequence":"additional","affiliation":[{"name":"Lerner Research Institute Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey A.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Ohashi","sequence":"additional","affiliation":[{"name":"Department of Oncology University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric C.","family":"Johannsen","sequence":"additional","affiliation":[{"name":"Department of Oncology University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon C.","family":"Kenney","sequence":"additional","affiliation":[{"name":"Department of Oncology University of Wisconsin School of Medicine 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,5,13]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.180.3.1171"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1500943"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.8.1521"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-0039.1999.530604.x"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-44905-z"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.101241"},{"key":"e_1_2_10_8_1","first-page":"5102","article-title":"Antitumor cytotoxicity mediated by ligand\u2010activated human Valpha24 NKT cells","volume":"59","author":"Kawano T","year":"1999","journal-title":"Cancer 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