Aberrant RNA sensing in regulatory T cells causes systemic autoimmunity.

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.

PMID: 38427731