Longitudinal liver sampling in patients with chronic hepatitis B starting antiviral therapy reveals hepatotoxic CD8+ T cells
Shirin Nkongolo, … , Harry L.A. Janssen, Adam J. Gehring
Shirin Nkongolo, … , Harry L.A. Janssen, Adam J. Gehring
Published January 3, 2023
Citation Information: J Clin Invest. 2023;133(1):e158903. https://doi.org/10.1172/JCI158903.
View: Text | PDF
Research Article Immunology Infectious disease

Longitudinal liver sampling in patients with chronic hepatitis B starting antiviral therapy reveals hepatotoxic CD8+ T cells

Abstract

Accumulation of activated immune cells results in nonspecific hepatocyte killing in chronic hepatitis B (CHB), leading to fibrosis and cirrhosis. This study aims to understand the underlying mechanisms in humans and to define whether these are driven by widespread activation or a subpopulation of immune cells. We enrolled CHB patients with active liver damage to receive antiviral therapy and performed longitudinal liver sampling using fine-needle aspiration to investigate mechanisms of CHB pathogenesis in the human liver. Single-cell sequencing of total liver cells revealed a distinct liver-resident, polyclonal CD8+ T cell population that was enriched at baseline and displayed a highly activated immune signature during liver damage. Cytokine combinations, identified by in silico prediction of ligand-receptor interaction, induced the activated phenotype in healthy liver CD8+ T cells, resulting in nonspecific Fas ligand–mediated killing of target cells. These results define a CD8+ T cell population in the human liver that can drive pathogenesis and a key pathway involved in their function in CHB patients.

Authors

Shirin Nkongolo, Deeqa Mahamed, Adrian Kuipery, Juan D. Sanchez Vasquez, Samuel C. Kim, Aman Mehrotra, Anjali Patel, Christine Hu, Ian McGilvray, Jordan J. Feld, Scott Fung, Diana Chen, Jeffrey J. Wallin, Anuj Gaggar, Harry L.A. Janssen, Adam J. Gehring

×

Figure 3

Hepatotoxic CD8+ T cells are a unique inflammatory and polyclonal CD8+ T cell population that downregulates immune-related genes as ALT levels decline.

Options: View larger image (or click on image) Download as PowerPoint
Hepatotoxic CD8+ T cells are a unique inflammatory and polyclonal CD8+ T...
Data pooled from all 5 patients. (A) Heatmap displaying a unique activated immunological signature of hepatotoxic CD8+ T cells at baseline. (B) Proportions of cells in the CD8+ T cell clusters out of all cells obtained at the respective time points. *P < 0.05; ****P < 0.0001, 2-sided z test to test for significant enrichment at baseline or week 24. 3,144 Cells make up the hepatotoxic CD8+ T cell population. (C and D) Numbers of differentially upregulated genes in each CD8+ T cell cluster when comparing baseline and week 12 (C) and baseline and week 24 (D). (E and F) Volcano plot showing genes that are differentially expressed over time by 12 weeks (E) and by 24 weeks (F) in the hepatotoxic CD8+ T cell population. Thresholds: P < 0.005 and fold change ≥ 1.3. Genes upregulated at baseline are shown to the right side of each plot. Genes downregulated at baseline are mainly ribosomal and mitochondrial genes. (G) Expression of immune-related genes in hepatotoxic CD8+ T cells from baseline to week 24. (H) UMAP plot of CD8+ T cell clusters at the time of active liver damage. (I) UMAP plot in (H) overlaid with the respective clonal sizes of TCR clonotypes.