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ResearchIn-Press PreviewImmunologyInflammation Open Access | 10.1172/jci.insight.199040

Hypomorphic Lig4 gene mutation in mice predisposes to Th1-skewed intestinal inflammation

Yusuke Yamashita,1 Hideki Kosako,1 Takashi Kato,2 Izumi Sasaki,2 Sadahiro Iwabuchi,3 Yuri Fukuda-Ohta,2 Tadashi Okamura,1 Misato Tane,1 Shotaro Tabata,1 Kazutaka Nakashima,4 Ken Tanaka,1 Kazunori Shiraishi,5 Yuki Uchihara,6 Daisuke Okuzaki,7 Kyoichi Isono,8 Atsushi Shibata,6 Tsunehiro Mizushima,9 Hiroaki Hemmi,2 Nobuo Kanazawa,10 Seiji Kodama,5 Hiroaki Miyoshi,4 Koichi Ohshima,4 Shinichi Hashimoto,3 Yoshio Fujitani,11 Takashi Sonoki,1 Shinobu Tamura,1 and Tsuneyasu Kaisho2

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

Find articles by Yamashita, Y. in: PubMed | Google Scholar

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

Find articles by Kosako, H. in: PubMed | Google Scholar

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

Find articles by Kato, T. in: PubMed | Google Scholar

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

Find articles by Sasaki, I. in: PubMed | Google Scholar

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

Find articles by Iwabuchi, S. in: PubMed | Google Scholar |

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

Find articles by Fukuda-Ohta, Y. in: PubMed | Google Scholar

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

Find articles by Okamura, T. in: PubMed | Google Scholar

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

Find articles by Tane, M. in: PubMed | Google Scholar

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

Find articles by Tabata, S. in: PubMed | Google Scholar

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

Find articles by Nakashima, K. in: PubMed | Google Scholar

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

Find articles by Tanaka, K. in: PubMed | Google Scholar

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

Find articles by Shiraishi, K. in: PubMed | Google Scholar

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

Find articles by Uchihara, Y. in: PubMed | Google Scholar

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

Find articles by Okuzaki, D. in: PubMed | Google Scholar |

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

Find articles by Isono, K. in: PubMed | Google Scholar

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

Find articles by Shibata, A. in: PubMed | Google Scholar

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

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1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

Find articles by Hemmi, H. in: PubMed | Google Scholar

1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

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1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

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1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

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1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

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1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

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1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

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1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

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1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

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1Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

2Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

3Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

4Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

5Laboratory of Radiation Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Osaka, Japan

6Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, Japan

7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka, Osaka, Japan

8Laboratory Animal Center, School of Medicine, Wakayama Medical University, Wakayama, Japan

9Graduate School of Science, University of Hyogo, Hyogo, Japan

10Department of Dermatology, Hyogo Medical University, Hyogo, Japan

11Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan

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Published September 1, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.199040.
Copyright © 2026, Yamashita et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 1, 2026 - Version history
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Abstract

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.

Graphical Abstract
graphical abstract
Supplemental material

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View Supplemental Table 1 Colon RNA-seq revised version

View Supplemental Table 2 GSEA reports

View Supplemental Table 3 Spleen RNA-Seq revised version

View Supplemental Table 4 MLN RNA-Seq revised version

View Supplemental Table 5 cluster annotation

View Supplemental Table 6 antibody 2nd revised version

View Supplemental Table 7 antibodies list ELISA revised version

View Supplemental Table 8 WT spleen matrix

View Supplemental Table 9 Homo1 spleen matrix

View Supplemental Table 10 Homo2 spleen matrix

View Supplemental Table 11 Homo3 spleen matrix

View Supplemental Table 12 WT TCR Clonotype table

View Supplemental Table 13 Homo1 TCR Clonotype table

View Supplemental Table 14 Homo2 TCR Clonotype table

View Supplemental Table 15 Homo3 TCR Clonotype table

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