{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T06:15:19Z","timestamp":1783318519609,"version":"3.54.6"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>\n                    Induced pluripotent stem cell (iPSC)-derived immune cells show promise for allogeneic immunotherapies. However, their clinical efficacy can be limited by early rejection of grafted iPSC-derived cells by host T cells and natural killer (NK) cells due to HLA mismatching. In theory, disrupting HLA class I expression can prevent T cell-mediated rejection, but, in its place, NK cells can eliminate \u201cmissing-self\u201d targets due to the absence of HLA-C and HLA-E. Therefore, we devised a strategy to extend the residence time of iPSC-derived invariant natural killer T (iPSC-derived iNKT) cells in humanized mice harboring allogeneic peripheral blood mononuclear cells (PBMCs) by genetically modifying HLA class I expression. To this end, we disrupted HLA class I expression by deleting the\n                    <jats:italic>\u03b22-microglobulin<\/jats:italic>\n                    (\n                    <jats:italic>B2M<\/jats:italic>\n                    ) gene, and then recapitulated HLA-C and\/or HLA-E expression in the iPSC-derived iNKT cells. Parental and modified iPSC-derived iNKT cells were assessed for their susceptibility to T- or NK cell-mediated cytotoxicity\n                    <jats:italic>in vitro<\/jats:italic>\n                    and for their residence time in allogeneic humanized mice.\n                    <jats:italic>In vitro<\/jats:italic>\n                    , dual co-expression of HLA-C and HLA-E facilitated escape from NK cell-mediated cytotoxicity, whereas single expression of either HLA-C or HLA-E provided inconsistent protection across NK cell donors. Since allogeneic HLA-C alleles can be recognized by T cells, we examined the impact of HLA-C mismatching on T cell-mediated cytotoxicity. T cell-mediated cytotoxicity against B2M-deficient iPSC-derived iNKT cells was restored when mismatched HLA-C was re-expressed.\n                    <jats:italic>In vivo<\/jats:italic>\n                    , B2M deficiency extended the residence time of iPSC-derived iNKT cells in allogeneic humanized mice. This effect was further enhanced by expression of HLA-C alleles matched to donor PBMCs, whereas expression of incompatible HLA-C reduced residence time. Taking into account the limitations of the humanized mouse model in recapitulating human NK cell function, these observations highlight the dominant role of T cell-mediated mechanisms in the rejection of allogeneic iPSC-derived iNKT cells\n                    <jats:italic>in vivo<\/jats:italic>\n                    . This study presents a promising approach for generating iPSC-derived iNKT cells tailored for a limited master cell bank, with the potential to develop universal off-the-shelf immunotherapy.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2026.1869698","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T05:38:16Z","timestamp":1783316296000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Extending the residence period of allogeneic iPSC-derived invariant natural killer T cells in humanized mice by editing HLA class I expression"],"prefix":"10.3389","volume":"14","author":[{"given":"Yun-Hsuan","family":"Chang","sequence":"first","affiliation":[{"name":"Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Aoki","sequence":"additional","affiliation":[{"name":"Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences","place":["Kanagawa, Japan"]},{"name":"Department of Medical Immunology, Graduate School of Medicine, Chiba University","place":["Chiba, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Momoko","family":"Okoshi","sequence":"additional","affiliation":[{"name":"Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Munechika","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Okura","sequence":"additional","affiliation":[{"name":"Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoko","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshie","family":"Sasako","sequence":"additional","affiliation":[{"name":"Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachiko","family":"Kira","sequence":"additional","affiliation":[{"name":"Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nayuta","family":"Yakushiji-Kaminatsui","sequence":"additional","affiliation":[{"name":"Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Omics Research, Department of Frontier Research and Development, Kazusa DNA Research Institute","place":["Chiba, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichiro","family":"Motohashi","sequence":"additional","affiliation":[{"name":"Department of Medical Immunology, Graduate School of Medicine, Chiba University","place":["Chiba, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruhiko","family":"Koseki","sequence":"additional","affiliation":[{"name":"Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2223","DOI":"10.1111\/cas.14428","article-title":"Activated invariant natural killer T cells directly recognize leukemia cells in a CD1d\u2010independent manner","volume":"111","author":"Aoki","year":"2020","journal-title":"Cancer Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/s41232-023-00275-5","article-title":"Regeneration of invariant natural killer T (iNKT) cells: application of iPSC technology for iNKT cell-targeted tumor immunotherapy","volume":"43","author":"Aoki","year":"2023","journal-title":"Inflamm. 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