2. Academic Validation
  3. Aberrant RNA sensing in regulatory T cells causes systemic autoimmunity

Aberrant RNA sensing in regulatory T cells causes systemic autoimmunity

  • Sci Adv. 2024 Mar;10(9):eadk0820. doi: 10.1126/sciadv.adk0820.
Domnica Luca 1,  Sumin Lee 2 3,  Keiji Hirota 1 4,  Yasutaka Okabe 5 6,  Junji Uehori 7,  Kazushi Izawa 8,  Anna-Lisa Lanz 9 10,  Verena Schütte 1,  Burcu Sivri 1,  Yuta Tsukamoto 1,  Fabian Hauck 9 10,  Rayk Behrendt 11,  Axel Roers 12,  Takashi Fujita 1 2 3,  Ryuta Nishikomori 13,  Min Ae Lee-Kirsch 14 15,  Hiroki Kato 1
Affiliations

Affiliations

  • 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.
PMID: 38427731 DOI: 10.1126/sciadv.adk0820
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 (Tregs) 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 Treg-specific deletion of Adar1 caused peripheral Treg loss and scurfy-like lethal autoimmune disorders. Similarly, knock-in mice with Treg-specific expression of an MDA5 gain-of-function mutant caused Apoptosis of peripheral Tregs and severe autoimmunity. Moreover, the impact of ADAR1 deficiency on Tregs is multifaceted, involving both MDA5 and PKR sensing. Together, our results highlight the dysregulation of Treg homeostasis by intrinsic aberrant RNA sensing as a potential determinant for type I interferonopathies.

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