Hypomorphic Lig4 gene mutation in mice predisposes to Th1-skewed intestinal inflammation
DNA ligase IV (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 have 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.
Authors
- Izumi Sasaki (ORCID: https://orcid.org/0000-0001-5080-8356)
- Daisuke Okuzaki (ORCID: https://orcid.org/0000-0002-4552-783X)
- Shinobu Tamura (ORCID: https://orcid.org/0000-0002-1150-0970)
- Nobuo Kanazawa (ORCID: https://orcid.org/0000-0003-3000-9711)
- Hiroaki Miyoshi (ORCID: https://orcid.org/0000-0002-2356-3725)
- Yusuke Yamashita (ORCID: https://orcid.org/0000-0002-9133-8183)
- S Tabata (ORCID: https://orcid.org/0000-0001-6240-4391)
- Yoshio Fujitani (ORCID: https://orcid.org/0000-0003-0196-4736)
- Sadahiro Iwabuchi (ORCID: https://orcid.org/0000-0003-0434-3054)
- Hiroaki Hemmi (ORCID: https://orcid.org/0009-0000-0938-0618)
- Kazutaka Nakashima (ORCID: https://orcid.org/0009-0007-6559-0362)
- Hideki Kosako
- Yuki Uchihara (ORCID: https://orcid.org/0000-0002-0052-6315)
- Tsuneyasu Kaisho (ORCID: https://orcid.org/0000-0003-2616-1665)
- Yuri Fukuda‐Ohta
- Misato Tane
- Tsunehiro Mizushima (ORCID: https://orcid.org/0000-0002-6631-2889)
- Tadashi Okamura (ORCID: https://orcid.org/0000-0001-8457-1561)
- Ken Tanaka (ORCID: https://orcid.org/0000-0002-6094-6522)
- Takashi Sonoki (ORCID: https://orcid.org/0000-0002-0211-3311)
- Seiji Kodama
- Kazunori Shiraishi
- Kyoichi Isono
- Koichi Ohshima
- Takashi Kato
- Atsushi Shibata
- Shinichi Hashimoto
Institutions
- Kurume University (JP)
- Gunma University (JP)
- University of Hyogo (JP)
- Wakayama Medical University (JP)
- Keio University (JP)
- Osaka International University (JP)
- Tokyo Metropolitan University (JP)
- Hyogo University (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- JCI Insight
- Published
- 2026-09-01
- DOI
- https://doi.org/10.1172/jci.insight.199040
- Primary Topic
- Genetic factors in colorectal cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- GlaxoSmithKline Japan
- Kowa Company
- Kowa Life Science Foundation
- Wakayama Medical University
- Japan Society for the Promotion of Science