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Kato group publishes article in Science Advances

Dysregulation of regulatory T cell homeostasis by ADAR1 deficiency and chronic MDA5 signaling

The research team of Prof. Dr. Hiroki Kato at the Institute of Cardiovascular Immunology is dedicated to understanding the intricate mechanisms of immune responses in the context of viral infections and autoimmune diseases. They are particularly interested in exploring how cytoplasmic RNA sensors, like MDA5, differentiate between viral RNAs and self-RNAs, initiating type I interferons (IFNs) as anti-viral defense. However, mutations in MDA5 can lead to autoimmune diseases. Complementary to that, Domnica Luca et al. recently published her findings in Science Advances with the title "Dysregulation of regulatory T cell homeostasis by ADAR1 deficiency and chronic MDA5 signaling."

ADAR1 deficiency constitutively activates MDA5 and causes type I IFN-driven autoimmune diseases. We found a significant reduction in the regulatory T cell (Treg) population in patients with type I interferonopathies caused by mutations in the ADAR1 or IFIH1 gene, encoding MDA5. We analyzed the underlying mechanisms using murine models and found that Treg-specific Adar1 deletion caused peripheral Treg loss and scurfy-like lethal autoimmune disorders. Treg-specific expression of MDA5 gain-of-function mutant also reduced the peripheral Treg population via apoptosis, resulting in severe autoimmune symptoms. However, shut-down of MDA5 signaling in Adar1-deficient Tregs still induced eIF-2α-mediated protein synthesis shut-off, leading to Treg loss and lethality. Altogether, our results highlight the dysregulation of Treg homeostasis in Adar1 deficiency as a key determinant for type I interferonopathies.

Domnica Luca AG Kato
Graphical Abstract
© Domnica Luca


Luca, D., et al. (2024)

Dysregulation of regulatory T cell homeostasis by ADAR1 deficiency and chronic MDA5 signaling

Science Advances

DOI: 10.1126/sciadv.adk0820

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