{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T18:09:34Z","timestamp":1793210974840,"version":"4.5.0"},"reference-count":33,"publisher":"American Society for Clinical Investigation","issue":"24","license":[{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Intramural Research Program NIH Clinical Center","award":["000-000-00"],"award-info":[{"award-number":["000-000-00"]}]},{"name":"Intramural Research Program, NIH National Institute of Allergy and Infectious Diseases","award":["000-000-00"],"award-info":[{"award-number":["000-000-00"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["AI001222"],"award-info":[{"award-number":["AI001222"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,22]]},"abstract":"<jats:p>\n                    The transcription factor IKAROS, encoded by\n                    <jats:italic>IKZF1<\/jats:italic>\n                    , is crucial for lymphocyte development and differentiation. Germline heterozygous\n                    <jats:italic>IKZF1<\/jats:italic>\n                    mutations cause B cell immunodeficiency, but also affect T cells. Patients with\n                    <jats:italic>IKZF1<\/jats:italic>\n                    haploinsufficiency (HI) or dimerization-defective (DD) variants show reduced naive and increased memory T cells, while dominant-negative (DN) mutations result in the opposite phenotype. Gain-of-function patients display variable patterns. To investigate IKAROS\u2019s role in shaping the human naive\/memory T cell phenotype, we performed IKAROS immunomodulation and knockdown experiments and analyzed early T cell development in an artificial thymic organoid (ATO) system using CD34\n                    <jats:sup>+<\/jats:sup>\n                    cells from patients with representative\n                    <jats:italic>IKZF1<\/jats:italic>\n                    variants. IKAROS inhibition by lenalidomide or silencing by small hairpin RNA directly altered expression of HNRNPLL, the master regulator of CD45 isoform splicing that defines CD45RA\n                    <jats:sup>+<\/jats:sup>\n                    \/naive and CD45RO\n                    <jats:sup>+<\/jats:sup>\n                    \/memory phenotypes. In the ATO system, IKAROS-DN precursor cells were blocked at the CD4\n                    <jats:sup>\u2013<\/jats:sup>\n                    CD8\n                    <jats:sup>\u2013<\/jats:sup>\n                    \/double-negative stage and retained a CD45RA\n                    <jats:sup>+<\/jats:sup>\n                    phenotype, whereas IKAROS-HI cells inefficiently reached the CD4\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    \/double-positive stage and partially transitioned from CD45RA to CD45RO. Analysis of public gene expression data showed high HNRNPLL expression in double-positive thymic cells, beyond the stages affected by\n                    <jats:italic>IKZF1<\/jats:italic>\n                    DN and HI mutations. Collectively, these findings indicate that IKAROS regulates early and late T cell development by mechanisms, including HNRNPLL modulation.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.197359","type":"journal-article","created":{"date-parts":[[2025,12,21]],"date-time":"2025-12-21T19:00:44Z","timestamp":1766343644000},"source":"Crossref","is-referenced-by-count":2,"title":["IKAROS regulates human T cell phenotype at a thymic and postthymic level"],"prefix":"10.1172","volume":"10","author":[{"given":"Jennifer","family":"Stoddard","sequence":"first","affiliation":[{"name":"Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2154-3966","authenticated-orcid":true,"given":"Hye Sun","family":"Kuehn","sequence":"additional","affiliation":[{"name":"Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravichandra","family":"Tagirasa","sequence":"additional","affiliation":[{"name":"Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marita","family":"Bosticardo","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Pala","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie E.","family":"Niemela","sequence":"additional","affiliation":[{"name":"Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agustin A.","family":"Gil Silva","sequence":"additional","affiliation":[{"name":"Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayla","family":"Amini","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Anaya","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Framil Seoane","sequence":"additional","affiliation":[{"name":"Immunology Department, Hospital Cl\u00ednic, Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Bouso","sequence":"additional","affiliation":[{"name":"Department of Immunology and Rheumatology, Juan P. Garrahan National Pediatric Hospital, Buenos Aires, Argentina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimana","family":"Dimitrova","sequence":"additional","affiliation":[{"name":"Center for Immuno-Oncology, National Cancer Institute, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A.","family":"Kanakry","sequence":"additional","affiliation":[{"name":"Center for Immuno-Oncology, National Cancer Institute, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3559-0018","authenticated-orcid":true,"given":"Laia","family":"Alsina","sequence":"additional","affiliation":[{"name":"Study Group for Immune Disfunction Diseases in Children, Institut de Recerca Sant Joan de D\u00e9u, Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de D\u00e9u, Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matias","family":"Oleastro","sequence":"additional","affiliation":[{"name":"Department of Immunology and Rheumatology, Juan P. 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