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-specific 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-specific 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 of Tregs. IL-10 production by conventional CD4 T cells and their CNS accumulation are rather elevated in Treg-specific 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-specific 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.

IL-27 targets Foxp3+ Tregs to mediate antiinflammatory functions during experimental allergic airway inflammation

“…Intranasal IL-27 administration fails to inhibit airway inflammation without Foxp3 + Tregs, and adoptive Foxp3 + Treg transfer restores the inhibition. We recently reported that Foxp3 + Tregs control the development of allergic airway inflammation and that IL-27 signaling in Foxp3 + Tregs is essential to control Th17-mediated autoimmune inflammation (19,20). Whether Tregs are essential during IL-27-mediated inhibition of allergic airway inflammation was next examined using Foxp3 DTR mice (23).…”

“…Allergen-induced allergic airway inflammation is exacerbated in Treg-specific Il27ra -/mice. To precisely determine the role of IL-27 signaling in Treg functions during allergic airway infiltration, Treg-specific Il27ra -/mice (Treg ΔIl27ra ) were next used (19). Treg ΔIl27ra and littermate Treg WT control mice were induced for allergic airway inflammation.…”

“…model system, that IL-27 signaling in Tregs plays an important role in limiting colitogenic Th1/Th17 type responses (28). Since this model requires a lymphopenic system to induce inflammation, we next developed Treg-specific Il27ra -/animal models and tested the role of IL-27 in Tregs during myelin antigen-reactive Th17 type autoimmune inflammation (19). Analogous to colitis models, we found that IL-27 signaling in Tregs plays an instrumental role in controlling Th1/Th17 type autoimmune inflammation.…”

“…However, IL-27 promotes T-bet and CXCR3 expression in Tregs that are specialized in controlling Th1-mediated immunity at local sites of inflammation (18), raising the possibility that IL-27 may play an important role in regulating Treg functions, especially during inflammation. We recently reported that IL-27 signaling in Foxp3 + Tregs is necessary to control Th17-mediated autoimmune inflammation (19). However, whether the IL-27/Treg axis is important in regulating Th2 associated allergic inflammation has not formally been tested.…”

“…Indeed, adoptive Treg transfer into endogenous Treg-depleted mice fully restored IL-27-mediated inhibition of allergic inflammation. IL-27 induces the lymphocyte activation gene 3 (Lag3) in Tregs (19), and Lag3 expression in Tregs was required for IL-27 to inhibit allergic inflammation. The findings that Treg-specific Il27ra -/mice develop severe allergic inflammation that is not attenuated by systemic IL-27 administration further support the key contribution of IL-27 in Treg functions.…”