Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset important in the early response to bacterial and viral lung pathogens. MAIT cells recognize bacterial small molecule metabolites presented on the Class I-like molecule MR1. As with other Class I and Class II molecules, MR1 can likely sample ligands in the intracellular environment through multiple cellular pathways. Rab6, a small GTPase that regulates a number of endosomal trafficking pathways including retrograde transport to the trans-Golgi network (TGN), is involved in the presentation of ligands from Mycobacterium tuberculosis (Mtb) to MAIT cells. The Rab6-mediated trafficking pathway contains endosomal compartments that share features with the Mtb intracellular compartment. Using inducible expression of MR1, this study demonstrates that Rab6 regulates the recycling of MR1 molecules from the cell surface through endosomal trafficking compartments to the TGN. This Rab6-dependent pool of recycled MR1, which is available for reloading with ligands from bacterial pathogens like Mtb, may be important for early recognition of infected cells by MAIT cells in the lung.
Chronic obstructive pulmonary disease (COPD) is associated with airway inflammation, increased infiltration by CD8+ T lymphocytes, and infection-driven exacerbations. COPD is most commonly caused by cigarette smoke (CS), however the mechanisms driving development of COPD in some smokers but not others are incompletely understood. Lung-resident mucosal-associated invariant T (MAIT) cells play a role in both microbial infections and inflammatory diseases. MAIT cell frequency is reduced in the peripheral blood of individuals with COPD, however the role of MAIT cells in COPD pathology is unknown. Here, we examined MAIT cell activation in response to CS-exposed primary human bronchial epithelial cells (BEC) from healthy, COPD, or smoker donors. We observed significantly higher MAIT cell responses to COPD BEC than healthy BEC. However, COPD BEC stimulated a smaller fold-increase in MAIT cell response despite increased microbial infection. For all donor groups, CS-exposed BEC elicited reduced MAIT cell responses; conversely, CS exposure increased ligand-mediated MR1 surface translocation in healthy and COPD BEC. Our data demonstrate MAIT cell activation is dysregulated in the context of CS and COPD. MAIT cells could contribute to CS- and COPD-associated inflammation through both inappropriate activation and reduced early recognition of bacterial infection, contributing to microbial persistence and COPD exacerbations.
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.
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