{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T15:21:11Z","timestamp":1792164071660,"version":"4.4.0"},"reference-count":59,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2015,8,18]],"date-time":"2015-08-18T00:00:00Z","timestamp":1439856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"U.S. Public Health Service National Institutes Health","award":["R21 HL102833-01"],"award-info":[{"award-number":["R21 HL102833-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title\/>\n                  <jats:p>Human embryonic stem cells (hESCs) are a promising source of cells for tissue regeneration, yet histoincompatibility remains a major challenge to their clinical application. Because the human leukocyte antigen class I (HLA-I) molecules are the primary mediators of immune rejection, we hypothesized that cells derived from a hESC line lacking HLA-I expression could be transplanted without evoking a robust immune response from allogeneic recipients. In the present study, we used the replacement targeting strategy to delete exons 2 and 3 of \u03b22-microglobulin on both gene alleles in hESCs. Because \u03b22-microglobulin serves as the HLA-I light chain, disruption of the \u03b22-microglobulin gene led to complete HLA-I deficiency on the cell surface of hESCs and their derivatives. Therefore, these cells were resistant to CD8+ T-cell-mediated destruction. Although interferon-\u03b3 (IFN-\u03b3) treatment significantly induced \u03b22-microglobulin expression, promoting CD8+ T cell-mediated killing of control hESCs and their derivatives, CD8+ T-cell-mediated cytotoxicity was barely observed with \u03b22-microglobulin-null hESCs and their derivatives treated with IFN-\u03b3. This genetic manipulation to disrupt HLA-I expression did not affect the self-renewal capacity, genomic stability, or pluripotency of hESCs. Despite being relatively sensitive to natural killer (NK) cell-mediated killing due to the lack of HLA-I expression, when transplanted into NK cell-depleted immunocompetent mice, \u03b22-microglobulin-null hESCs developed into tumors resembling those derived from control hESCs in severe combined immunodeficiency mice. These results demonstrate that \u03b22-microglobulin-null hESCs significantly reduce immunogenicity to CD8+ T cells and might provide a renewable source of cells for tissue regeneration without the need for HLA matching in the future.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Significance<\/jats:title>\n                  <jats:p>This study reports the generation of a novel \u03b22-microglobulin (B2M)\u2212\/\u2212 human embryonic stem cell (hESC) line. Differentiated mature cells from this line do not express cell surface human leukocyte antigen molecules even after interferon-\u03b3 stimulation and are resistant to alloreactive CD8+ T cells. Moreover, this B2M\u2212\/\u2212 hESC line contains no off-target integration or cleavage events, is devoid of stable B2M mRNA, exhibits a normal karyotype, and retains its self-renewal capacity, genomic stability, and pluripotency. Although B2M\u2212\/\u2212 hESC-derived cells are more susceptible to natural killer (NK) cells, murine transplantation studies have indicated that they are, overall, much less immunogenic than normal hESCs. Thus, these data show for the first time that, in vivo, the advantages provided by B2M\u2212\/\u2212 hESC-derived cells in avoiding CD8+ T-cell killing appear significantly greater than any disadvantage caused by increased susceptibility to NK cells.<\/jats:p>\n               <\/jats:sec>","DOI":"10.5966\/sctm.2015-0049","type":"journal-article","created":{"date-parts":[[2015,8,19]],"date-time":"2015-08-19T03:29:17Z","timestamp":1439954957000},"page":"1234-1245","source":"Crossref","is-referenced-by-count":175,"title":["Targeted Disruption of the <i>\u03b2<\/i>2-Microglobulin Gene Minimizes the Immunogenicity of Human Embryonic Stem Cells"],"prefix":"10.1093","volume":"4","author":[{"given":"Dachun","family":"Wang","sequence":"first","affiliation":[{"name":"The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Medical School at Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Quan","sequence":"additional","affiliation":[{"name":"The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Medical School at Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Yan","sequence":"additional","affiliation":[{"name":"The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Medical School at Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John E.","family":"Morales","sequence":"additional","affiliation":[{"name":"The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Medical School at Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rick A.","family":"Wetsel","sequence":"additional","affiliation":[{"name":"The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Medical School at Houston, Houston, Texas, USA"},{"name":"Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,8,18]]},"reference":[{"key":"2021122704421720800_R1","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1126\/science.282.5391.1145","article-title":"Embryonic stem cell lines derived from human blastocysts","volume":"282","author":"Thomson","year":"1998","journal-title":"Science"},{"key":"2021122704421720800_R2","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/74447","article-title":"Embryonic stem cell lines from human blastocysts: Somatic differentiation in 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