Landscape of Immune Cells Heterogeneity in Liver Transplantation by Single-Cell RNA Sequencing Analysis

Abstract

Rejection is still a critical barrier to the long-term survival of graft after liver transplantation, requiring clinicians to unveil the underlying mechanism of liver transplant rejection. The cellular diversity and the interplay between immune cells in the liver graft microenvironment remain unclear. Herein, we performed single-cell RNA sequencing analysis to delineate the landscape of immune cells heterogeneity in liver transplantation. T cells, NK cells, B cells, and myeloid cell subsets in human liver and blood were enriched to characterize their tissue distribution, gene expression, and functional modules. The proportion of CCR6+CD4+ T cells increased within an allograft, suggesting that there are more memory CD4+ T cells after transplantation, in parallel with exhausted CTLA4+CD8+ T and actively proliferating MKI67+CD8+ T cells increased significantly, where they manifested heterogeneity, distinct function, and homeostatic proliferation. Remarkably, the changes of CD1c+ DC, CADM+ DC, MDSC, and FOLR3+ Kupffer cells increase significantly, but the proportion of CD163+ Kupffer, APOE+ Kupffer, and GZMA+ Kupffer decreased. Furthermore, we identified LDLR as a novel marker of activated MDSC to prevent liver transplant rejection. Intriguingly, a subset of CD4+CD8+FOXP3+ T cells included in CTLA4+CD8+ T cells was first detected in human liver transplantation. Furthermore, intercellular communication and gene regulatory analysis implicated the LDLR+ MDSC and CTLA4+CD8+ T cells interact through TIGIT-NECTIN2 signaling pathway. Taken together, these findings have gained novel mechanistic insights for understanding the immune landscape in liver transplantation, and it outlines the characteristics of immune cells and provides potential therapeutic targets in liver transplant rejection.

Analysis of cuproptosis in hepatocellular carcinoma using multi-omics reveals a comprehensive HCC landscape and the immune patterns of cuproptosis

“…Single cell analysis was carried out following the previous study ( 22 ). The Seurat R package (version 3.2.0) ( 23 ), a tool for single cell genomics, was utilized to process single cell RNA sequencing data.…”

Revisiting transplant immunology through the lens of single-cell technologies

“…The first study on human liver transplantation and rejection has been recently published [ 84 ]. Li and colleagues analyzed 55 liver allograft biopsies, 7 livers (3 = health and 4 = liver transplantation), and 4 PBMC specimens.…”

“…Finally, the increased presence of CCR6 + CD4 + T cell in the graft might suggest the presence of a higher proportion of memory T cells along with DC cells in the liver after transplantation. Interestingly, the author described the presence of a novel CD4 + CD8 + FOXP3 + T cell population in the context of liver transplantation [ 84 ].…”

Cancer Risk and Mutational Patterns Following Organ Transplantation

“…Li et al mapped the heterogeneity of immune cells after liver transplantation for the first time by single-cell sequencing and other techniques. T cells and myeloid cells showed different tissue distribution and function in human liver and peripheral blood ( Li et al, 2022 ). Yang et al sequenced about 20,000 cells of normal and steatotic donor liver tissue after transplantation by single-cell sequencing technology and drew the first single-cell map of steatotic transplanted liver ( Yang et al, 2021 ).…”