Early IL-6 signalling promotes IL-27 dependent maturation of regulatory T cells in the lungs and resolution of viral immunopathology

Abstract

Interleukin-6 is a pleiotropic, pro-inflammatory cytokine that can promote both innate and adaptive immune responses. In humans with respiratory virus infections, such as Respiratory Syncytial Virus (RSV), elevated concentrations of IL-6 are associated with more severe disease. In contrast the polymorphisms in the Il6 promoter which favour lower IL-6 production are associated with increased risk of both RSV and Rhinovirus infections. To determine the precise contribution of IL-6 to protection and pathology we used murine models of respiratory virus infection. RSV infection resulted in increased IL-6 production both in the airways and systemically which remained heightened for at least 2 weeks. IL-6 depletion early, but not late, during RSV or Influenza A virus infection resulted in significantly increased disease associated with an influx of virus specific T _H1 and cytotoxic CD8 ⁺ T cells, whilst not affecting viral clearance. IL-6 acted by driving production of the immunoregulatory cytokine IL-27 by macrophages and monocytes, which in turn promoted the local maturation of regulatory T cells. Concordantly IL-27 was necessary to regulate T _H1 responses in the lungs, and sufficient to limit RSV induced disease. Overall we found that during respiratory virus infection the prototypic inflammatory cytokine IL-6 is a critical anti-inflammatory regulator of viral induced immunopathology in the respiratory tract through its induction of IL-27.

Author summary

In clearing a respiratory virus, the host must strike a careful balance between the need to clear the infection and the potential of the immune response to damage the delicate structure of the lungs. Here we show that Interleukin-6, a soluble mediator commonly associated with inflammation and seen in humans with severe respiratory infection, is actually critical in promoting the resolution of the host response to respiratory virus infection and limiting disease. We have found that the early production of IL-6 after infection promotes the production of the regulatory mediator Interleukin-27 by lung resident immune cells, which in turn drives suppression of otherwise damaging inflammation. Removal of either IL-6 or IL-27 enhances disease during viral infection, while restoration of IL-27 is sufficient to allow faster recovery. Thus we have identified a novel immunological network within the respiratory tract which accelerates recovery after respiratory virus infection.