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).
