The respiratory tract is an important site of immune regulation; required to allow protective immunity against pathogens, while minimizing tissue damage and avoiding aberrant inflammatory responses to inhaled allergens. Several cell types work in concert to control pulmonary immune responses and maintain tolerance in the respiratory tract, including regulatory and effector T cells, airway and interstitial macrophages, dendritic cells and the airway epithelium. The cytokines transforming growth factor β, interleukin (IL-) 10, IL-27, and IL-35 are key coordinators of immune regulation in tissues such as the lung. Here, we discuss the role of these cytokines during respiratory infection and allergic airway disease, highlighting the critical importance of cellular source and immunological context for the effects of these cytokines in vivo.

Understanding how immune challenges elicit different responses is critical for diagnosing and deciphering immune regulation. Using a modular strategy to interpret the complex transcriptional host response in mouse models of infection and inflammation, we show a breadth of immune responses in the lung. Lung immune signatures are dominated by either IFN-γ and IFN-inducible, IL-17-induced neutrophil- or allergy-associated gene expression. Type I IFN and IFN-γ-inducible, but not IL-17- or allergy-associated signatures, are preserved in the blood. While IL-17-associated genes identified in lung are detected in blood, the allergy signature is only detectable in blood CD4 + effector cells. Type I IFN-inducible genes are abrogated in the absence of IFN-γ signaling and decrease in the absence of IFNAR signaling, both independently contributing to the regulation of granulocyte responses and pathology during Toxoplasma gondii infection. Our framework provides an ideal tool for comparative analyses of transcriptional signatures contributing to protection or pathogenesis in disease.

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 play a vital role orchestrating pulmonary homeostasis and defense against pathogens. TGF-β 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-β acts as a pro-viral factor suppressing early immune responses during influenza A infection. Mice specifically lacking bronchial epithelial TGF-β1 (epTGFβKO) 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 IFNβ release into the airways was significantly enhanced in epTGFβKO mice compared to control mice, with elevated IFNβ at day 1 in epTGFβKO compared to control mice. This induced a heighted anti-viral state resulting in impaired viral replication in epTGFβKO mice.Thus, epithelial derived TGF-β acts to suppress early IFNβ responses leading to increased viral burden and pathology. This study demonstrates the importance of the local epithelial micro-environmental niche in shaping initial immune responses to viral infection and controlling host disease.