Hepatic cholinergic T cell signaling mediates an adaptive response to alcohol-induced liver stress
- 1University of Michigan
Abstract
Alcohol-associated liver disease (ALD) is a major cause of liver-related morbidity and mortality, yet no targeted, disease-modifying therapy exists and the immune mechanisms driving disease progression remain poorly defined. Acetylcholine-producing cholinergic immune cells have emerged as regulators of homeostasis across tissues and in disease, but their role in alcohol-induced hepatic stress is unknown. Here, we characterized the hepatic cholinergic immune landscape during alcohol-induced stress using flow cytometry and single-cell RNA-sequencing of ChAT-eGFP reporter mice. Alcohol feeding expanded hepatic cholinergic immune cells, with T cells constituting a substantial and dynamic fraction of this population that showed a broad increase in acetylcholine signaling and shifted towards a repressed, anergy-like transcriptional state. CD4 T cells underwent coordinated suppression of cholesterol biosynthesis, while CD8 T cells instead adopted a cytotoxic activation program. Together, these findings identify cholinergic T cell signaling, and cholesterol metabolism within CD4 T cells specifically, as a previously unrecognized adaptive response to alcohol-induced liver stress, nominating candidate therapeutic targets for a disease that is marred by critically limited treatment options.
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BibTeX
@misc{knights2026hepatic,
title = {{Hepatic cholinergic T cell signaling mediates an adaptive response to alcohol-induced liver stress}},
author = {A. J. Knights and S. Liu and E. J. Kim and J. Wu},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.18.752097},
url = {https://www.biorxiv.org/content/10.64898/2026.09.18.752097v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Hepatic cholinergic T cell signaling mediates an adaptive response to alcohol-induced liver stress
AU - A. J. Knights
AU - S. Liu
AU - E. J. Kim
AU - J. Wu
PY - 2026
DA - 2026/09/18
PB - bioRxiv
DO - 10.64898/2026.09.18.752097
UR - https://www.biorxiv.org/content/10.64898/2026.09.18.752097v1
AB - Alcohol-associated liver disease (ALD) is a major cause of liver-related morbidity and mortality, yet no targeted, disease-modifying therapy exists and the immune mechanisms driving disease progression remain poorly defined. Acetylcholine-producing cholinergic immune cells have emerged as regulators of homeostasis across tissues and in disease, but their role in alcohol-induced hepatic stress is unknown. Here, we characterized the hepatic cholinergic immune landscape during alcohol-induced stress using flow cytometry and single-cell RNA-sequencing of ChAT-eGFP reporter mice. Alcohol feeding expanded hepatic cholinergic immune cells, with T cells constituting a substantial and dynamic fraction of this population that showed a broad increase in acetylcholine signaling and shifted towards a repressed, anergy-like transcriptional state. CD4 T cells underwent coordinated suppression of cholesterol biosynthesis, while CD8 T cells instead adopted a cytotoxic activation program. Together, these findings identify cholinergic T cell signaling, and cholesterol metabolism within CD4 T cells specifically, as a previously unrecognized adaptive response to alcohol-induced liver stress, nominating candidate therapeutic targets for a disease that is marred by critically limited treatment options.
ER -