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ResearchIn-Press PreviewImmunologyNephrology Open Access | 10.1172/JCI208155

Transcriptional regulation of NK cell state by ELF4 links innate immune licensing to kidney fibrosis

Shen Li,1 Hailong Hu,1 Zachary R. Lanzar,2 Xiangchen Gu,1 Elisa Cruz-Morales,2 Audrey C. Bochi-Layec,3 Andrea Sanchez-Navarro,1 Jihwan Park,1 Rojesh Shrestha,1 Hongbo Liu,1 Aaron J. Donner,4 Meei-Hua Lin,5 Thomas A. Bell,4 Jeffrey H. Miner,5 Marco Ruella,3 Eric Vivier,6 Carrie L. Lucas,7 Christopher A. Hunter,2 and Katalin Susztak1

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

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

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

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

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

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1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

Find articles by Gu, X. in: PubMed | Google Scholar

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

Find articles by Cruz-Morales, E. in: PubMed | Google Scholar

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

Find articles by Bochi-Layec, A. in: PubMed | Google Scholar

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

Find articles by Sanchez-Navarro, A. in: PubMed | Google Scholar

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

Find articles by Park, J. in: PubMed | Google Scholar

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

Find articles by Shrestha, R. in: PubMed | Google Scholar

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

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

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

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

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

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

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

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

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

Find articles by Miner, J. in: PubMed | Google Scholar |

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

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

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

Find articles by Vivier, E. in: PubMed | Google Scholar

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

Find articles by Lucas, C. in: PubMed | Google Scholar

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

Find articles by Hunter, C. in: PubMed | Google Scholar |

1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, United States of America

3Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Ionis Pharmaceuticals Inc., Carlsbad, United States of America

5Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

6CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France

7Immunobiology Department, Yale University School of Medicine, New Haven, United States of America

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

Published November 12, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI208155.
Copyright © 2026, Li 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 November 12, 2026 - Version history
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Abstract

Fibrosis is a common outcome of chronic tissue injury, yet immune regulators that are conserved across species and translatable to human disease remain poorly defined. By integrating human kidney transcriptomes with multiple murine models of kidney fibrosis, we identified the ETS transcription factor ELF4 as a conserved, immune-enriched regulator associated with disease severity. ELF4 expression was highest in natural killer (NK) cells. Genetic deletion of Elf4, including NK cell–specific ablation, attenuated experimental kidney injury, with reduced inflammation, fibrosis, and loss of renal function. Single-cell and functional analyses showed that ELF4 deficiency disrupts late-stage NK cell maturation and broadly suppresses cytotoxic and interferon-γ (IFNγ) effector programs. Mechanistically, ELF4 directly sustains STAT1 transcription, maintaining a STAT1–TBX21 program required for NK cell maturation and effector competence. Consistent with this framework, NK cell depletion, IFNγ neutralization, or antisense-mediated suppression of Elf4 phenocopied renal protection. Together, these findings identify ELF4 as a transcriptional licensing factor that links NK cell state to kidney injury and highlight innate immune programming as a potential therapeutic entry point in chronic kidney disease.

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