MAIT cell function in response to airway epithelial cells is dysregulated in the context of cigarette smoke and COPD

Abstract

Abstract MAIT cells are a subset of innate-like lung-resident CD8+ T cells that are thought to play a role in early immune responses to airway infections. These cells exhibit immediate effector function following recognition of bacterial small molecule metabolites presented on the MHC Class I-like molecule, MR1. The impact of cigarette smoke and the development of COPD on MR1 and MAIT cell function is unknown. To address this, we obtained primary airway epithelial cells from the lungs of human subjects with COPD (n=6) or healthy controls (n=6). These cells were treated or not with cigarette smoke extract (CSE), infected with S. pneumoniae, and then used as antigen presenting cells in an IFN-γ ELISPOT assay with a MAIT cell clone. We found that MAIT cells produced more IFN-γ when incubated with uninfected cells from COPD lungs compared to healthy lungs, suggesting that the development of COPD could result in an increase in antigen-independent MAIT cell responses. In contrast, only treatment with CSE impacted antigen-dependent MAIT cell responses to S. pneumoniae-infected airway epithelial cells. Collectively, the differences in MAIT cells responses could not be explained by differences in bacterial infection or MR1 expression in the airway epithelial cells between groups. Dysfunctional MAIT cell responses in the airways could contribute to COPD-associated inflammation by inappropriately activating pro-inflammatory pathways. Furthermore, reduced early recognition of bacterial infection by MAIT cells in the context of cigarette smoke could contribute to persistent colonization of the lower airways and exacerbations.