IFNγ regulates MR1 transcription and antigen presentation

Abstract

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.