Signal Transducer and Activator of Transcription ( <scp>STAT</scp> ) Proteins Regulate Mucosal‐Associated Invariant T ( <scp>MAIT</scp> ) Cell Function

Mucosal-Associated Invariant T (MAIT) cells are a subset of T cells with potential for rapid cytotoxic and inflammatory functions. Dysregulation of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway, particularly involving STAT1 and STAT3, has been implicated in MAIT cell dysfunction in certain diseases. However, the transcriptional mechanisms regulating their effector functions, particularly the role of various STAT proteins, remain poorly understood. Using RNA sequencing and proteomics data, and experimental validation through in vitro assays using MAIT-specific stimulation and small molecule inhibitors, we analysed the impact of STAT1, STAT3 and STAT5 on MAIT cell activation and function. Flow cytometric analysis was used to assess the functional implications of manipulating STAT proteins and the metabolic regulator HIF1α in MAIT cells. Our findings show that enhanced STAT1 activity negatively impacts MAIT cell effector functions, including granzyme B and interferon-γ expression, while STAT3 and STAT5 are essential for promoting MAIT cell activation, function and glycolytic responses. Additionally, we identify HIF1α as a key regulator of these processes, suggesting that metabolic reprogramming plays a critical role in MAIT cell activation and function. This study highlights the critical roles of STAT1, STAT3, STAT5 and HIF1α in regulating MAIT cell effector functions, expanding our understanding of the molecular mechanisms underlying MAIT cell dysfunction. Our work lays the foundation for future research and applications aimed at modulating MAIT cell activity in immune-related diseases and malignancies.