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

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 th1 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 th1 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. © 2017 pyle et al.