Hypomorphic Lig4 gene mutation in mice predisposes to Th1-skewed intestinal inflammation
15 affiliations
- 1Department of Hematology/Oncology
- 2Department of Immunology, Institute of Advanced Medicine
- 3Department of Rheumatology and Clinical Immunology, and
- 4Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan.
- 5Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan.
- 6Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan.
- 7Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan.
- 8Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan.
- 9Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan.
- 10Graduate School of Science, University of Hyogo, Hyogo, Japan.
- 11Laboratory of Immunology, Faculty of Veterinary Medicine, Okayama University of Science, Ehime, Japan.
- 12Department of Dermatology, Hyogo Medical University, Hyogo, Japan.
- 13Laboratory of Developmental Biology and Metabolism, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan.
- 14First Department of Internal Medicine and
- 15Industry-Government-Academia Collaboration Promotion Headquarters, Wakayama Medical University, Wakayama, Japan.
Abstract
DNA ligase IV (LIGIV or LIG4) is essential for DNA double-strand break (DSB) repair. Hypomorphic LIG4 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 Lig4 mutant mice. However, no model mice with defective DSB repair have consistently exhibited inflammation. Here, we generated mutant mice carrying the LIG4 missense variant, p.W447C, found in a patient with LIG4 syndrome. Lig4W447C/W447C 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-γ–inducible genes. When Ifng 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 Lig4W447C/W447C mice preferentially used proximal Vα and Jα segments in V regions of TCRα chains and exhibited expansion of several clonotypes, a substantial portion of which were CD4+ T cells expressing IFN-γ. Thus, our hypomorphic Lig4 mutant mice represent a unique model for studying Th1-skewed intestinal inflammation under severe adaptive immunodeficiency.
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BibTeX
@article{yamashita2026hypomorphic,
title = {{Hypomorphic Lig4 gene mutation in mice predisposes to Th1-skewed intestinal inflammation}},
author = {Yusuke Yamashita and Hideki Kosako and Takashi Kato and Izumi Sasaki and Sadahiro Iwabuchi and Yuri Fukuda-Ohta and Tadashi Okamura and Misato Tane and Shotaro Tabata and Kazutaka Nakashima and Ken Tanaka and Kazunori Shiraishi and Yuki Uchihara and Daisuke Okuzaki and Kyoichi Isono and Atsushi Shibata and Tsunehiro Mizushima and Hiroaki Hemmi and Nobuo Kanazawa and Seiji Kodama and Hiroaki Miyoshi and Koichi Ohshima and Shinichi Hashimoto and Yoshio Fujitani and Takashi Sonoki and Shinobu Tamura and Tsuneyasu Kaisho},
journal = {JCI Insight},
year = {2026},
month = sep,
doi = {10.1172/jci.insight.199040},
url = {https://doi.org/10.1172/jci.insight.199040},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Hypomorphic Lig4 gene mutation in mice predisposes to Th1-skewed intestinal inflammation
AU - Yusuke Yamashita
AU - Hideki Kosako
AU - Takashi Kato
AU - Izumi Sasaki
AU - Sadahiro Iwabuchi
AU - Yuri Fukuda-Ohta
AU - Tadashi Okamura
AU - Misato Tane
AU - Shotaro Tabata
AU - Kazutaka Nakashima
AU - Ken Tanaka
AU - Kazunori Shiraishi
AU - Yuki Uchihara
AU - Daisuke Okuzaki
AU - Kyoichi Isono
AU - Atsushi Shibata
AU - Tsunehiro Mizushima
AU - Hiroaki Hemmi
AU - Nobuo Kanazawa
AU - Seiji Kodama
AU - Hiroaki Miyoshi
AU - Koichi Ohshima
AU - Shinichi Hashimoto
AU - Yoshio Fujitani
AU - Takashi Sonoki
AU - Shinobu Tamura
AU - Tsuneyasu Kaisho
PY - 2026
DA - 2026/09/01
JO - JCI Insight
DO - 10.1172/jci.insight.199040
UR - https://doi.org/10.1172/jci.insight.199040
AB - DNA ligase IV (LIGIV or LIG4) is essential for DNA double-strand break (DSB) repair. Hypomorphic LIG4 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 Lig4 mutant mice. However, no model mice with defective DSB repair have consistently exhibited inflammation. Here, we generated mutant mice carrying the LIG4 missense variant, p.W447C, found in a patient with LIG4 syndrome. Lig4W447C/W447C 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-γ–inducible genes. When Ifng 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 Lig4W447C/W447C mice preferentially used proximal Vα and Jα segments in V regions of TCRα chains and exhibited expansion of several clonotypes, a substantial portion of which were CD4+ T cells expressing IFN-γ. Thus, our hypomorphic Lig4 mutant mice represent a unique model for studying Th1-skewed intestinal inflammation under severe adaptive immunodeficiency.
SN - 2379-3708
ER -