Single Cell Multi‐Omics Revealing the Important Role of MR1 Mediated MAIT Cells in Maintaining Rejection for Liver Transplantation

Mucosal-associated invariant T (MAIT) cells, representing one of the most abundant subsets of unconventional T cells, have been shown to play a significant role in regulating immune responses. However, their immunoregulatory roles in the context of liver transplantation (LT) immunity remain largely undefined. To address this, we conducted single-cell RNA/TCR sequencing, flow cytometry, and multiplex immunohistochemical (mIHC) assays to identify the proportion and characteristics of CD8+ MAIT cells in humans and mice following liver transplantation. We found that CD8+ MAIT cells were prominently represented in the single-cell CD8 profiles of human transplanted livers, demonstrating strong signalling associations with macrophages, whilst the fractional populations of MAIT1 and MAIT17 were distinctly clustered. In parallel, the proportion of CD8+ MAIT cells was significantly elevated in mouse LT models, revealing a dynamic trend where percentages increased at 1 and 2 weeks post-transplant, peaking at 3 weeks. Furthermore, using established MR1 knockout (MR1KO) LT mice, we observed that mice lacking MAIT cells exhibited milder rejection responses, indicating that MR1 mediates rejection by influencing the remodelling of the TCR repertoire after transplantation. Collectively, our study reveals that MAIT cells play a critical role in LT rejection, as MR1KO alleviated inflammatory responses and mitigated rejection via TCR repertoire remodelling. By mapping the dynamic changes of MAIT cells throughout the rejection process, these findings lay the groundwork for further investigations into the role of these cells in transplant immunity.