Journal
MUCOSAL IMMUNOLOGY
Volume 11, Issue 2, Pages 523-535Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mi.2017.77
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Funding
- Welcome Trust [087618/Z/08/Z, 107059/Z/15/Z]
- MRC
- Asthma UK Centre in Allergic Mechanisms of Asthma
- Asthma UK [MRC-Asthma UK Centre, MRC-AsthmaUKCentre] Funding Source: researchfish
- Medical Research Council [G1000758, G1000758B] Funding Source: researchfish
- Wellcome Trust [087618/Z/08/Z, 107059/Z/15/Z] Funding Source: Wellcome Trust
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Mucosal surfaces are under constant bombardment from potentially antigenic particles and so must maintain a balance between homeostasis and inappropriate immune activation and consequent pathology. Epithelial cells have a vital role orchestrating pulmonary homeostasis and defense against pathogens. TGF-beta regulates an array of immune responses-both inflammatory and regulatory-however, its function is highly location-and context-dependent. We demonstrate that epithelial-derived TGF-beta acts as a pro-viral factor suppressing early immune responses during influenza A infection. Mice specifically lacking bronchial epithelial TGF-beta 1 (epTGF beta KO) displayed marked protection from influenza-induced weight loss, airway inflammation, and pathology. However, protection from influenza-induced pathology was not associated with a heightened lymphocytic immune response. In contrast, the kinetics of interferon beta (IFN beta) release into the airways was significantly enhanced in epTGFbKO mice compared with control mice, with elevated IFN beta on day 1 in epTGF beta KO compared with control mice. This induced a heighted antiviral state resulting in impaired viral replication in epTGF beta KO mice. Thus, epithelial-derived TGF-beta acts to suppress early IFN beta responses leading to increased viral burden and pathology. This study demonstrates the importance of the local epithelial microenvironmental niche in shaping initial immune responses to viral infection and controlling host disease.
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