Aberrant RNA sensing in regulatory T cells causes systemic autoimmunity-Reference-Cited by-同舟云学术

Aberrant RNA sensing in regulatory T cells causes systemic autoimmunity

Published:2024-03 Issue:9 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Luca Domnica¹^ORCID,Lee Sumin²³,Hirota Keiji¹⁴^ORCID,Okabe Yasutaka⁵⁶^ORCID,Uehori Junji⁷^ORCID,Izawa Kazushi⁸^ORCID,Lanz Anna-Lisa⁹¹⁰^ORCID,Schütte Verena¹,Sivri Burcu¹^ORCID,Tsukamoto Yuta¹^ORCID,Hauck Fabian⁹¹⁰^ORCID,Behrendt Rayk¹¹^ORCID,Roers Axel¹²^ORCID,Fujita Takashi¹²³,Nishikomori Ryuta¹³^ORCID,Lee-Kirsch Min Ae¹⁴¹⁵^ORCID,Kato Hiroki¹^ORCID

Affiliation:

1. Institute of Cardiovascular Immunology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.

2. Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.

3. Laboratory of Regulatory Information, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.

4. Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.

5. Laboratory of Immune Homeostasis, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.

6. Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan.

7. Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.

8. Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9. Division of Pediatric Immunology and Rheumatology, Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.

10. Munich Centre for Rare Diseases (M-ZSE), University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.

11. Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.

12. Institute of Immunology, University of Heidelberg, Heidelberg, Germany.

13. Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan.

14. Department of Pediatrics, University Hospital Carl Gustav Carus and Medical Faculty, Technische Universität Dresden, Dresden, Germany.

15. University Center for Rare Diseases, University Hospital Carl Gustav Carus and Medical Faculty, Technische Universität Dresden, Dresden, Germany.

Abstract

Chronic and aberrant nucleic acid sensing causes type I IFN–driven autoimmune diseases, designated type I interferonopathies. We found a significant reduction of regulatory T cells (T regs ) in patients with type I interferonopathies caused by mutations in ADAR1 or IFIH1 (encoding MDA5). We analyzed the underlying mechanisms using murine models and found that T reg -specific deletion of Adar1 caused peripheral T reg loss and scurfy -like lethal autoimmune disorders. Similarly, knock-in mice with T reg -specific expression of an MDA5 gain-of-function mutant caused apoptosis of peripheral T regs and severe autoimmunity. Moreover, the impact of ADAR1 deficiency on T regs is multifaceted, involving both MDA5 and PKR sensing. Together, our results highlight the dysregulation of T reg homeostasis by intrinsic aberrant RNA sensing as a potential determinant for type I interferonopathies.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adk0820

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