Aberrant RNA sensing in regulatory T cells causes systemic autoimmunity

• Published in: Science advances Vol. 10; no. 9; p. eadk0820
• Main Authors: Luca, Domnica, Lee, Sumin, Hirota, Keiji, Okabe, Yasutaka, Uehori, Junji, Izawa, Kazushi, Lanz, Anna-Lisa, Schütte, Verena, Sivri, Burcu, Tsukamoto, Yuta, Hauck, Fabian, Behrendt, Rayk, Roers, Axel, Fujita, Takashi, Nishikomori, Ryuta, Lee-Kirsch, Min Ae, Kato, Hiroki
• Format: Journal Article
• Language: English
• Published: United States 01.03.2024
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adk0820

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