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 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.

Airway macrophages as the guardians of tissue repair in the lung

“…Conversely, PGE 2 administration reversed this phenotype . AM‐derived IL‐6 is a critical mediator of viral‐induced immunopathology and plays an important role in the pulmonary tract by facilitating recruitment of Ly6C hi monocytes and induction and maturation of Tregs via IL‐27 signaling . In a model of influenza virus infection, AM‐derived TRAIL expression induced epithelial cell death, which is thought to represent a preemptive host defense mechanism to decrease susceptibility to infection by IAV.…”

Cytokines and CD8 T cell immunity during respiratory syncytial virus infection

“…The peak of the RSV-specific CD8 T cell response correlates with complete viral clearance from the lung between 8 and 10 days following a primary RSV infection ( Fig. 1a) [15,18,34,35,42,43]. Infection of athymic nude mice, which lack T cells, results in a persistent infection in which the virus is detectable for at least 20 days post-infection [43,44].…”

“…Antibody-mediated blockade of IL-17 in vivo enhances the total numbers of RSV-specific CD8 T cells and CD8 T cells producing IFN-γ or granzyme B in the lung following RSV infection [17]. IL-27 also suppresses CD8 T cell cytokine production in the airways, as the numbers of CD8 T cells producing IFN-γ and both IFN-γ and TNF are significantly increased in mice treated with an IL-27 neutralizing antibody [18]. Blockade of IL-6 also significantly elevates the total number of pulmonary RSV-specific CD8 T cells compared to IgG-treated controls [18].…”

“…IL-27 also suppresses CD8 T cell cytokine production in the airways, as the numbers of CD8 T cells producing IFN-γ and both IFN-γ and TNF are significantly increased in mice treated with an IL-27 neutralizing antibody [18]. Blockade of IL-6 also significantly elevates the total number of pulmonary RSV-specific CD8 T cells compared to IgG-treated controls [18]. Interestingly, IL-6 blockade prior to day 3 post-infection has a more profound effect on the enhancement of RSVspecific CD8 T cell numbers than later antibody treatment.…”

“…Interferon-γ (IFN-γ) and tumor necrosis factor (TNF) secreted by CD8 T cells contribute to viral clearance but can also mediate immunopathology following RSV infection [12][13][14][15]. In contrast, CD8 T cell activation and effector functions are inhibited by the actions of a variety of cytokines, including interleukin-10 (IL-10) and IL-4 [16][17][18][19]. Here we review the current literature on CD8 T cell responses following RSV infection and discuss the role of cytokines produced by CD8 T cells in both protecting against and exacerbating RSV-induced disease.…”