Search

Mucosal associated invariant T (MAIT) cells were first identified as specific for bacterial, mycobacterial, and fungal organisms, which detect microbially-derived biosynthetic ligands presented by MHC-related protein 1 (MR1). More recently two unexpected, additional roles have been identified for these ancient and abundant cells: a TCR-depen-dent role in tissue repair and a TCR-independent role in antiviral host defence. Data from several classes of viral disease shows their capability for activation by the cytokines interleukin (IL)-12, IL-15, IL-18, and type I interferon. MAIT cells are abundant at mucosal surfaces, particularly in the lung, and it seems likely a primary reason for their striking evolutionary conservation is an important role in early innate defence against respiratory infections, including both bacteria and viruses. Here we review evidence for their TCR-independent activation, observational human data for their activation in influenza A virus, and in vivo murine evidence of their protection against severe influenza A infection, mediated at least partially via IFN-gamma. We then survey evidence emerging from other respiratory viral infections including recent evidence for an important adjuvant role in adenovirus infection, specifically chimpanzee adenoviruses used in recent coronavirus vaccines, and data for strong associations between MAIT cell responses and adverse outcomes from coronavirus-19 (COVID-19) disease. We speculate on potential translational implications of these findings, either using corticosteroids or inhibitory ligands to suppress deleterious MAIT cell responses, or the potential utility of stimulatory MR1 ligands to boost MAIT cell frequencies to enhance innate viral defences.

BackgroundAlthough several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear.ObjectiveWe sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients.MethodsAn IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS–specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens.ResultsActivation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS–high asthma with increased epithelial expression of IL-6TS–inducible genes in the absence of systemic inflammation. The IL-6TS–high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β.ConclusionsLocal lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.