Lust, T. N. | bioRxiv Science

bioRxiv2025

IFNγ regulates MR1 transcription and antigen presentation

Antigen presentation molecules play key roles in activating T cell immunity. Multiple complementary pathways are known to regulate classical MHC-I molecules at transcriptional, translational, and post-translational levels. Intracellular trafficking mechanisms dictating post-transcriptional regulation of MR1, the MHC Class I-like molecule which restricts MAIT cells, have been an area of focus; however, little is known about MR1 transcriptional regulation. We demonstrate that, similar to classical MHC-I, interferons regulate MR1 transcription. Treatment of airway epithelial cells (AEC) with recombinant IFN{beta} or IFN{gamma} variably increased MR1 transcripts, while only IFN{gamma} significantly increased surface MR1 expression and enhanced antigen presentation to MAIT cells. The MR1 promoter contains binding motifs for interferon regulatory factor 1 (IRF1), an important MHC-I transcription factor. IRF1 knockout reduced IFN{gamma}-stimulated MR1 transcription, surface expression, and antigen presentation. Conversely, knockout of Nod-like Receptor family CARD domain containing 5 (NLRC5), a critical component of IFN{gamma}-induced MHC-I transcription, did not significantly impact MR1 expression. These findings were corroborated in primary human AEC treated with IFN{gamma}. In co-culture experiments, MAIT cells incubated with Streptococcus pneumoniae-infected primary AEC produced sufficient IFN{gamma} to stimulate upregulation of MR1 expression. Our data support a model where IFN{gamma} from activated MAIT cells or another source stimulates IRF1-dependent MR1 expression and antigen presentation, leading to greater MAIT cell activation. A robust MR1-dependent MAIT cell response may be beneficial for early infection responses, allowing minimal antigen stimulus to generate greater proinflammatory activity.

immunology↗

bioRxiv2022

Chronic obstructive pulmonary disease and cigarette smoke exposure lead to dysregulated MAIT cell activation by bronchial epithelial cells

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.

immunology↗