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Hypomorphic\n                    <jats:italic>LIG4<\/jats:italic>\n                    variants cause LIG4 syndrome, characterized by growth disturbance, increased radiosensitivity, predisposition to malignancies, adaptive immunodeficiency, and inflammatory conditions. Most of these manifestations are recapitulated in hypomorphic\n                    <jats:italic>Lig4<\/jats:italic>\n                    mutant mice. However, no model mice with defective DSB repair have consistently exhibited inflammation. Here, we generated mutant mice carrying the\n                    <jats:italic>LIG4<\/jats:italic>\n                    missense variant, p.W447C, found in a patient with LIG4 syndrome.\n                    <jats:italic>\n                      Lig4\n                      <jats:sup>W447C\/W447C<\/jats:sup>\n                    <\/jats:italic>\n                    mice showed functional defects of LIGIV and manifested growth retardation, increased radiosensitivity, and life-threatening intestinal inflammation under severe adaptive immunodeficiency. The inflammation was dependent on lymphocytes and characterized by marked infiltration of Th1 cells and macrophages, along with elevated expression of IFN-\u03b3\u2013inducible genes. When\n                    <jats:italic>Ifng<\/jats:italic>\n                    was deleted, Th2 and Th17 instead of Th1 cells drove the inflammation. Single-cell RNA-seq analyses with TCR repertoire revealed that T cells from\n                    <jats:italic>\n                      Lig4\n                      <jats:sup>W447C\/W447C<\/jats:sup>\n                    <\/jats:italic>\n                    mice preferentially used proximal V\u03b1 and J\u03b1 segments in V regions of TCR\u03b1 chains and exhibited expansion of several clonotypes, a substantial portion of which were CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells expressing IFN-\u03b3. Thus, our hypomorphic\n                    <jats:italic>Lig4<\/jats:italic>\n                    mutant mice represent a unique model for studying Th1-skewed intestinal inflammation under severe adaptive immunodeficiency.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.199040","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T16:04:18Z","timestamp":1788278658000},"source":"Crossref","is-referenced-by-count":1,"title":["Hypomorphic Lig4 gene mutation in mice predisposes to Th1-skewed intestinal inflammation"],"prefix":"10.1172","volume":"11","author":[{"given":"Yusuke","family":"Yamashita","sequence":"first","affiliation":[{"name":"Department of Hematology\/Oncology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Kosako","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute of Advanced Medicine,"},{"name":"Department of Rheumatology and Clinical Immunology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izumi","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute of Advanced Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0434-3054","authenticated-orcid":true,"given":"Sadahiro","family":"Iwabuchi","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Fukuda-Ohta","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute 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