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

PLoS Pathogens

David P. Swieboda¹  James A. Harker²  Faith I. Uwadiae²  Chloe J. Pyle² 

[1] MRC & Asthma UK Centre in Allergic Mechanisms for Asthma, London, United Kingdom;Section of Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London, South Kensington Campus, South Kensington, London, United Kingdom

关键词: T cells;    Regulatory T cells;    Respiratory infections;    Cytotoxic T cells;    Alveolar macrophages;    Neutrophils;    Cytokines;    Influenza A virus;   

DOI  :  10.1371/journal.ppat.1006640

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY