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 IFNβ, IFNγ, and IFNλ variably increased MR1 transcripts, while only IFNγ significantly increased surface MR1 expression and enhanced antigen presentation to MAIT cells. ChIP-PCR confirmed that Interferon Regulatory Factor 1 (IRF1), an important MHC-I transcription factor, binds to the MR1 promoter. IRF1 knockout reduced IFNγ-stimulated MR1 transcription, surface expression, and antigen presentation. Conversely, knockout of Nod-like Receptor family CARD domain containing 5 (NLRC5), a critical component of IFNγ-induced MHC-I transcription, did not significantly impact MR1 expression. These findings were corroborated in primary human AEC treated with IFNγ. In co-culture experiments, MAIT cells incubated with Streptococcus pneumoniae-infected primary AEC produced sufficient IFNγ to stimulate upregulation of MR1 expression. Cigarette smoke is known to modulate transcription of molecules involved in peptide antigen generation and loading (eg TAP1, immunoproteasome). Cigarette smoke treatment of infected primary AEC decreased the MR1 expression induced by co-culture with activated MAIT cells. Our data support a model where IFNγ 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 early after infection, allowing minimal antigen stimulus to generate greater proinflammatory activity. External assaults like cigarette smoke could disrupt this regulatory mechanism, delaying early responses to microbes, ultimately contributing to pathological inflammation like that observed in chronic obstructive pulmonary disease (COPD).