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Comparative analysis of liver tissues from heahtly mice and mice suffering from cholangitis

ABSTRACT: The goal of the study was to compare the transcriptomic signature (by bulk RNA-sequencing) of hepatic tissues of mice either healthy/normal or affected with primary sclerosing cholangitis (PSC) or primary biliary cholangitis mouse (PBC) (Paillet et al, J Exp Med, 2021). Transcriptomic analyses revealed mostly convergent alterations in the gene expression patterns when PBC and PSC were compared to normal, age- and sex-matched controls. Gene Ontology (GO) term analyses of the modulated mRNAs revealed a significant enrichment of genes involved in inflammation, immune response and chemotaxis of different leukocyte subsets . The expression of genes listed under the GO terms “inflammation” and “neutrophil” was not significantly different (p>0.5, Student t-test) between PBC and PSC. In sharp contrast, genes listed under the GO terms “T cell” and “B cell” were significantly (p<0.05, Student t-test) upregulated in PBC compared to PSC livers. Deeper analysis of the aforementioned liver RNA-seq dataset indicated that several genes specifically involved in Th1 and Tc1 responses were upregulated in PBC livers with respect to controls and, in some cases also with respect to PSC. Especially, this applies to Tc1-related genes encoding the markers CD8a, CD274 (best known as PD-L1), UL16 binding protein 1 (ULBP1), IFNγ, G Protein-Coupled Receptor 18 (GPR18), the transcription factor suppressor of cytokine signaling 1 (SOCS1), and the cytotoxic protease granzyme B (GzmB) (Paillet et al, J Exp Med, 2021).

ORGANISM(S): Mus musculus

PROVIDER: GSE179993 | GEO | 2021/08/28

REPOSITORIES: GEO

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Project description:We report in this study the expansion of T cell clonotypes inflitrating both ectopic cholangiocarcinoma (CCA) and liver tissues in a mouse suffering from primary biliary cholangitis (PBC) (Paillet et al, J Exp Med, 2021). We wondered whether the specificity of T cells found in PBC livers and tumors developing post-PBC might be shared to some extent, comparing them to circulating T cells from the blood (Paillet et al, J Exp Med, 2021). Single-cell TCR sequencing coupled to single-cell RNA sequencing (scTCR/RNA-seq) led to the identification of 8112 distinct clonotypes with a hierarchy of clonotypes enrichment that was significantly higher in PBC livers than in peripheral blood, as well as in CCA compared to blood and liver. Indeed, 12 distinct clonotypes accounted for ~20% of the tumor T cell infiltrate. The overlap of clonotypes between liver and tumor was superior to the overlap between blood and liver, or blood and tumor. Among the 128 clonotypes enriched (i.e. accounting for > 0.1% of total T cells infiltrating the tissue) in the tumor, 25 were also detected and enriched in the liver. Two clonotypes (#2 and #13) were particularly expanded, each representing over 0.5% of the total T cell population in both liver and tumor post-PBC (Paillet et al, J Exp Med, 2021). Bioinformatic analysis of the scRNA-seq data of total T cells isolated from the liver and tumor of a PBC mouse revealed a net distinction between the transcriptome of T lymphocytes located in the two organs. Only one phenotypic cluster (h) was observed in both liver and tumor. The 25 liver/tumor dual-enriched (>0.1%) clonotypes were spread across few clusters (mostly c, j, k in the tumor; b and i in the liver). Among these clusters, three corresponded to CD8+ T cells (c, i, k) and two corresponded to CD4+ T cells (b, j). They exhibited a preponderant Tc1/Th1 polarization as illustrated by the expression of the enhancers Tbx21 and/or Eomes, and of effector molecules, namely IFNγ for Th1 (b, j), or the cytotoxic markers granzymes B and K for Tc1 (c, i, k) (Paillet et al, J Exp Med, 2021). Interestingly, the two clusters containing most of the enriched CD4+ T cell clonotypes presented a multifunctional signature characterized by the co-expression of IFNγ along with either IL4 (cluster b in the liver) or GzmB and KLRG1 (cluster j in the tumor). Clearly, the two most enriched clonotypes shared between CCA tumor and PBC liver belonged to the category of CD8+ cytotoxic T lymphocytes (clusters c + k in tumor, and cluster i in the liver). Moreover, they showed signs of prolonged activation/exhaustion with the expression of Pdcd1 (encoding PD-1), Lag3, Harvc2/Tim3 and Tigit, yet in a lesser extent than another cluster of CD8+ T cells (tumor cluster f) that contains only little shared clonotypes (Paillet et al, J Exp Med, 2021).

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Comparative analysis of liver tissues from heahtly mice and mice suffering from cholangitis

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