Unveiling the Role of Mucosal-Associated Invariant T Cells in Peritoneal Fibrosis and Its Therapeutic Targeting

Background: One of the most common causes of discontinued peritoneal dialysis (PD) is progressive peritoneal fibrosis. Persistent low-grade inflammation induced by PD treatment is a driving force of peritoneal fibrogenesis. Mucosal-associated invariant T (MAIT) cells, known for their role in immune responses against microbial infections, have also been implicated in various inflammatory and fibrotic diseases. Despite their known importance, the specific mechanisms through which MAIT cells contribute to peritoneal fibrosis remain poorly understood. Methods: Utilizing single-cell RNA sequencing (scRNA-seq) and flow cytometry, we characterized the activation and function of peritoneal MAIT cells from patients receiving long-term peritoneal dialysis (PD). We explored the molecular pathways activated by these cells, focusing on the MR1-mediated interaction with mesothelial cells and the subsequent activation of the mTORC1 signaling pathway. The effects of MAIT cell inhibition on fibrogenesis were examined using both in vitro models and Mr1 knockout mice. Results: Our findings indicate that long-term PD enhances the activation of MAIT cells, specifically increasing the population of pro-inflammatory MAIT17 subtype cells. These cells contribute to peritoneal fibrosis by binding to the MR1 receptor on mesothelial cells, inducing hyperglycolysis via the mTORC1 pathway, which leads to peritoneal fibrogenesis. Furthermore, we demonstrate that blocking the MR1-MAIT interaction, either through genetic knockout or pharmacological inhibition with Ac-6-FP, mitigates fibrosis, suggesting a novel therapeutic strategy. Conclusion: This study underscores the crucial role of MAIT cells in the pathogenesis of peritoneal fibrosis and identifies them as potential targets for therapeutic intervention. The findings suggest that while some aspects of MAIT cell involvement in fibrosis are beginning to be understood, comprehensive insights into their roles in various pathological conditions remain limited, warranting further investigation.