IFNαR signaling in effector but not regulatory T cells is required for immune dysregulation during type I IFN-dependent inflammatory disease

Abstract

Type I IFNs are a family of proinflammatory cytokines that are essential for antiviral immunity but whose overexpression is associated with several autoimmune disorders. In this study, we asked how chronic IFN overexpression regulates the activity of different cell types and how this contributes to immune dysfunction during IFN-associated inflammatory diseases. We show that in mice that chronically overproduce type I IFNs owing to loss of the DNA exonuclease Trex1, inflammatory disease completely depends on IFNαR signaling in T cells. Although IFNs directly inhibited the proliferation and activation of Foxp3(+) regulatory T cells, this was neither required nor sufficient for development of inflammatory disease. Rather, chronic IFN expression directly promoted the expansion and activation of effector T cells, and disease development was completely dependent on IFNαR signaling in these cells. Thus, chronic IFN expression can drive inflammatory disease via its direct effects on effector, but not regulatory, T cells.