Background & Aims: Little is known about the composition of intrahepatic immune cells
and their contribution to the pathogenesis of primary sclerosing cholangitis (PSC).
Herein, we aimed to create an atlas of intrahepatic T cells and thereby perform an
in-depth characterization of T cells in inflamed human liver. Methods: Different single-cell
RNA sequencing methods were combined with in silico analyses on intrahepatic and peripheral
T cells from patients with PSC (n = 11) and healthy donors (HDs, n = 4). Multi-parameter
flow cytometry and functional in vitro experiments were conducted on samples from
patients with PSC (n = 24), controls with other liver diseases and HDs. Results: We
identified a population of intrahepatic naive-like CD4(+) T cells, which was present
in all liver diseases tested, but particularly expanded in PSC. This population had
a transcriptome and T cell receptor repertoire similar to circulating naive T cells
but expressed a set of genes associated with tissue residency. Their periductal location
supported the concept of tissue-resident naive-like T cells in livers of patients
with PSC. Trajectory inference suggested that these cells had the developmental propensity
to acquire a T helper 17 (T(H)17) polarization state. Functional and chromatin accessibility
experiments revealed that circulating naive T cells in patients with PSC were predisposed
to polarize towards T(H)17 cells. Conclusion: We report the first atlas of intrahepatic
T cells in PSC, which led to the identification of a previously unrecognized population
of tissue-resident naive-like T cells in the inflamed human liver and to the finding
that naive CD4(+) T cells in PSC harbour the propensity to develop into T(H)17 cells.
Lay summary: The composition of intrahepatic immune cells in primary sclerosing cholangitis
(PSC) and their contribution to disease pathogenesis is widely unknown. We analysed
intrahepatic T cells and identified a previously uncharacterized population of liver-resident
CD4(+) T cells which are expanded in the livers of patients with PSC compared to healthy
liver tissue and other liver diseases. These cells are likely to contribute to the
pathogenesis of PSC and could be targeted in novel therapeutic approaches. (C) 2021
The Authors. Published by Elsevier B.V. on behalf of European Association for the
Study of the Liver.
