Granzyme profiles in CXCR6+PD-1+CD8+T cells differentiate acute and chronic hepatitis flares and may reflect intrahepatic immune imprints

Previously, we demonstrated that circulating CXCR6+PD-1+CD8+T cells correlate with liver damage in patients with ALT flares (GASL 2024). Further understanding of these cells’ phenotypic and transcriptional profiles may reveal their role in disease pathogenesis.

We analyzed blood CD8+T cells in 63 patients with ALT levels≥5x ULN, including 24 with acute viral hepatitis (16 HBV), 16 with chronic viral hepatitis (15 HBV), and 23 non-viral cases (mainly autoimmune hepatitis). Public single-cell RNA sequencing data (blood and liver CD8+T cells) from HBV-infected patients were reanalyzed to investigate transcriptional patterns.

Circulating CXCR6+PD-1+CD8+T cells exhibited distinct granzyme expression. Acute hepatitis was associated with high GZMB expression while resolving acute and chronic hepatitis showed high GZMK levels. UMAP analysis revealed that intrahepatic CD8+T cells predominantly transcribe GZMK while circulating CD8+T cells mainly transcribe GZMB. A subset of circulating cells, marked by high CXCR6, HLA-DRA, and PDCD1 transcription, shared transcriptional similarities with intrahepatic cells. This subset exhibited high co-transcription of immunomodulatory and checkpoint genes, activation markers, CREM, and GZMK. Trajectory analysis identified an intermediate state of CXCR6+CD8+T cells transitioning between liver and blood, characterized by a shift in granzyme expression between GZMB and GZMK.

In conclusion, CXCR6+PD-1+CD8+T cells show different granzyme profiles in ALT flares between acute and chronic hepatitis. We suggest that the initial inflammatory response is dominated by the expression of GZMB, followed by a transcriptional shift towards GZMK, reflecting the developing intrahepatic immune dynamics (i.e. CREM expression).

Publication History

Article published online:
20 January 2025