Extensive evidence supports the pivotal role of CD8+Tregs in transplantation and immunological disorders (Yao et al., 2017, Dai et al., 2014). CD8+T cells exhibiting high CD45RC expression are indicative of acute rejection or graft-versus-host disease (GVHD) in transplant patients (Lemerle et al., 2019, Garnier et al., 2019). Consequently, the CD8+T cell subset with slightly low to negative CD45RC expression, referred to as CD8+CD45RClow/-Tregs, has garnered increasing attention from transplant physicians and immunologists (Picarda et al., 2017, Bézie et al., 2018). Elevated levels of CD8+CD45RClow/-Tregs have shown a close correlation with immune tolerance in cardiac allografts (Picarda et al., 2017). Our previous research has demonstrated that CD8+CD45RClow/-Tregs can mediate immune tolerance through IFN-γ, and the adoptive transfer of these Tregs induces long-term graft survival in a rat model of cardiac allograft (Li et al., 2010). In our unpublished work, a distinct subset of CD8+CD45RClow/-Tregs exhibiting high expression of MHC-class II molecules (MHC-II) was observed in the grafts and spleens of an immune tolerance rat cardiac transplantation model, along with a significant increase in plasmacytoid dendritic cells (pDCs) and IFN-γ. However, it remains unclear whether CD8+CD45RClow/-Tregs positive for MHC-II (MHC-II+CD8+CD45RClow/-Tregs) play a key role in tolerance induction and how they are generated.

Previous studies have substantiated the transfer of MHC molecules from donor antigen-presenting cells (APCs) to receptor immune cells' surface via trogocytosis (Liu et al., 2016, Ono et al., 2018). Trogocytosis involves one cell physically extracting and ingesting "bites" of cellular material from another cell (Joly and Hudrisier, 2003). Initially observed in eukaryotic microbes, trogocytosis was identified as a mechanism by which amoebae eliminate cells. This process has the potential to represent a crucial type of cell-cell interaction in eukaryotes. Trogocytosis is not confined to unicellular organisms but also manifests in multicellular organisms, playing pivotal roles in the immune system, central nervous system, and developmental processes (Bettadapur et al., 2020). Liu et al. (2016) demonstrated that, in mouse cardiac transplantation, host dendritic cells (DCs) acquire intact donor MHC molecules from donor DCs. Ono et al. (2018) noted that host DCs acquiring intact donor MHC molecules in grafts play a pivotal role in alloimmunity regulation and the promotion of liver transplant tolerance. Additionally, CD8+T cells were reported to acquire MHC-I or II molecules from APCs through trogocytosis mediated by ligand-receptor interactions (Romagnoli et al., 2013, Jia et al., 2021). Therefore, we propose that MHC-II expression in MHC-II+CD8+CD45RClow/-Tregs might be acquired from pDCs through trogocytosis, presenting significant potential to mediate donor-specific immune tolerance.

To test this hypothesis, we initially re-evaluated the role of MHC-II+CD8+CD45RClow/-Tregs in a rat model of spontaneous immune tolerance liver transplant. Subsequently, we investigated the generation mechanism of this cell in vitro through co-culture and further explored the immunomodulatory function of MHC-II+CD8+CD45RClow/-Tregs. We aspire that our findings will pave the way for developing a novel approach to induce donor-specific suppression in clinical transplants through adoptive transfer.