Attenuation of regulatory T cell function by type I IFN signaling in an MDA5 gain-of-function mutant mouse model.

Melanoma differentiation-associated gene 5 (MDA5) is an essential viral double-stranded RNA sensor to trigger antiviral immune responses, including type I interferon (IFN) induction. Aberrant activation of this viral sensor is known to cause autoimmune diseases designated as type I interferonopathies. However, the cell types responsible for these diseases and the molecular mechanisms behind their onset and development are still largely unknown. In this study, we revealed the attenuation of regulatory T cell (Treg) function by type I IFN signaling in a mouse model expressing a gain-of-function MDA5 G821S mutant. We found that experimental colitis induced by adoptive transfer of naïve T cells in Rag2 −/− mice was rescued by simultaneous transfer of Tregs from wild-type but not from the MDA5 mutant mice. Type I IFN receptor deficiency in the MDA5 mutant mice recovered the suppressive function of MDA5 mutant Tregs. These results suggest that constitutive MDA5 and type I IFN signaling in Tregs decreases the suppressive function of Tregs, potentially contributing to the onset and exacerbation of autoimmune disorders in interferonopathies. • The suppressive function of Tregs is monitored in an experimental colitis model. • Constitutive MDA5 signaling dysregulates the suppression activity of Tregs. • Type I IFN signaling is critical for the malfunction of MDA5 gain-of-function mutant Tregs. [ABSTRACT FROM AUTHOR]