engleski

IL-33-dependent immunosuppressive Treg responses to liver damage during MCMV infection

Host responses to viral infections involve complex interactions between cytokines and chemokines that provide communication signals resulting in the development of effective innate and adaptive immunity. Murine cytomegalovirus (MCMV) is a herpesvirus with pathogenic potential that can induce high levels of viral replication and modulate antiviral responses. Thus, early immune mechanisms are essential in controlling virus replication and protecting the host from virus- induced pathology. Interleukin-33 (IL-33) is a pro-inflammatory cytokine, expressed in the nucleus of nonhematopoetic cells, such as fibroblasts, endothelial and epithelial cells at barrier sites. It functions as an endogenous danger signal, alarmin, in response to tissue damage. Although its receptor, ST2, is expressed by many immune cells, it is highest on activated Th2 and mast cells where it participates in type 2 immunity and inflammation. However, signaling through ST2 exerts pleiotropic effects towards different cell types and it also amplifies CD8+ T cell (CTL) responses to viral infection, such as LCMV. In addition, it is necessary for IFN-γ production by NK cells. Here we show that ST2- deficient mice have weaker NK and CTL responses to MCMV infection than control wild-type mice. This indicates that IL-33 amplifies both NK and CTL responses to MCMV. In spite of this, ST2- deficient mice showed normal viral control, suggesting compensatory mechanism induced in absence of ST2 signaling. Moreover, ST2- deficient mice infected with high dose of MCMV showed higher death rate which is mediated by stronger liver pathology. This is a consequence of decreased infiltration od Treg cells and lower expression of anti-inflammatory IL-10 and TGF-β, compared to control mice. In the light of recent discovery of IL-33's importance for accumulation and maintenance of Treg cells in acute colitis model, our results suggest protective and homeostatic role of IL-33 signaling in inflammation induced by MCMV infection.

IL-33; immunoregulation; mouse cytomegalovirus; ST2 receptor

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