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

Foxp3⁺ CD4 Tregs are central regulators of inflammation, including allergic inflammation in the lung. There is increasing evidence that inflammatory factors undermine adequate Treg functions and homeostasis, resulting in prolonged and exacerbated inflammation. Therefore, identifying the factors is of the utmost important. IL-27 is an antiinflammatory cytokine implicated in immune regulation and tolerance. However, the cellular mechanisms underlying IL-27–mediated immune regulation in vivo remain largely unknown. Utilizing a cockroach antigen–induced allergic inflammation model in mice, we sought to test the roles of Tregs during IL-27–mediated regulation of allergic inflammation. Intranasally delivered IL-27 significantly reduced the development of airway inflammation. Unexpectedly, the IL-27–induced reduction occurred only in the presence of Tregs. Il27ra^–/– and Treg-specific Il27ra^–/– mice developed severe airway inflammation, and IL-27 treatment had little impact on diminishing the inflammatory responses. IL-27–induced treatment was restored following transfer of WT Tregs but not of Tregs deficient in Lag3, a molecule induced by IL-27 in Tregs. Finally, Tregs from asthmatic patients exhibited blunted STAT1 phosphorylation following IL-27 stimulation. Taken together, our results uncover that Tregs are the primary target cells of IL-27 in vivo to mediate its antiinflammatory functions, suggesting that altered IL-27 responsiveness in Tregs may underlie inadequate Treg functions and perpetuation of inflammation.