Dissecting the immune discrepancies in mouse liver allograft tolerance and heart/kidney allograft rejection

The liver is the most tolerogenic of transplanted organs. However, the mechanisms underlying liver transplant tolerance are not well understood. The comparison between liver transplantation tolerance and heart/kidney transplantation rejection will deepen our understanding of tolerance and rejection in solid organs. Here, we built a mouse model of liver, heart and kidney allograft and performed single-cell RNA sequencing of 66,393 cells to describe the cell composition and immune cell interactions at the early stage of tolerance or rejection. We also performed bulk RNA-seq of mouse liver allografts from Day 7 to Day 60 post-transplantation to map the dynamic transcriptional variation in spontaneous tolerance. The transcriptome of lymphocytes and myeloid cells were characterized and compared in three types of organ allografts. Cell-cell interaction networks reveal the coordinated function of Kupffer cells, macrophages and their associated metabolic processes, including insulin receptor signalling and oxidative phosphorylation in tolerance induction. Cd11b+ dendritic cells (DCs) in liver allografts were found to inhibit cytotoxic T cells by secreting anti-inflammatory cytokines such as Il10. In summary, we profiled single-cell transcriptome analysis of mouse solid organ allografts. We characterized the immune microenvironment of mouse organ allografts in the acute rejection state (heart, kidney) and tolerance state (liver). Here, we established mouse models of liver, heart and kidney transplantation. We performed single-cell analysis of the allografts at the early phase of rejection/tolerance as well as bulk RNA analysis of long-term tolerance in liver allograft at different time point. We compared gene expression patterns of the immune microenvironment in organ allografts. We identified coordinated function of macrophages and associated metabolic process including insulin receptor signaling and oxidative phosphorylation process in liver transplantation tolerance induction.image