Aberrant RNA sensing in regulatory T cells causes systemic autoimmunity

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 <i>ADAR1</i> or <i>IFIH1</i> (encoding MDA5). We analyzed the underlying mechanisms using murine models and found that T_reg-specific deletion of <i>Adar1</i> caused peripheral T_reg loss and <i>scurfy</i>-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.