Treg-specific IL-27Rα deletion uncovers a key role for IL-27 in Treg function to control autoimmunity

Abstract

Dysregulated Foxp3+Treg functions result in uncontrolled immune activation and autoimmunity. Therefore, identifying cellular factors modulating Treg functions is an area of great importance. Here, using Treg-specificIl27ra−/−mice, we report that IL-27 signaling in Foxp3+Tregs is essential for Tregs to control autoimmune inflammation in the central nervous system (CNS). Following experimental autoimmune encephalomyelitis (EAE) induction, Treg-specificIl27ra−/−mice develop more severe EAE. Consistent with the severe disease, the numbers of IFNγ- and IL-17–producing CD4 T cells infiltrating the CNS tissues are greater in these mice. Treg accumulation in the inflamed CNS tissues is not affected by the lack of IL-27 signaling in Tregs, suggesting a functional defect ofIl27ra−/−Tregs. IL-10 production by conventional CD4 T cells and their CNS accumulation are rather elevated in Treg-specificIl27ra−/−mice. Analysis with Treg fate-mapping reporter mice further demonstrates that IL-27 signaling in Tregs may control stability of Foxp3 expression. Finally, systemic administration of recombinant IL-27 in Treg-specificIl27ra−/−mice fails to ameliorate the disease even in the presence of IL-27–responsive conventional CD4 T cells. These findings uncover a previously unknown role of IL-27 in regulating Treg function to control autoimmune inflammation.