CD8 TRM-like T cells expressing perforin and IFN-γ define a pediatric activated T-cell acute liver failure endotype
Year: 2026
Type: article
Abstract: BACKGROUND: Activated T-cell pediatric acute liver failure (TC-PALF) is the most common cause of non-acetaminophen PALF, with poor transplant-free survival. Livers in TC-PALF are infiltrated by effector cytotoxic T lymphocytes with markers of tissue-resident memory function (CD8 Trm) and an interferon gamma (IFNγ) transcriptional signature. The PALF-Immune Response Network (PALF-IRN) and the prospective TReatment for ImmUne-Mediated PathopHysiology (TRIUMPH) clinical trial (NCT04862221) aim to characterize the TC-PALF immune pathology and utility of T-cell directed therapy to improve transplant-free survival. METHODS: TRIUMPH patients with TC-PALF were compared with healthy children and disease controls utilizing multiparameter flow cytometry and 3' single-cell RNA sequencing from peripheral blood mononuclear cells. TC-PALF patient serum was compared with healthy children and those with PALF from other causes, utilizing the Olink Inflammation I 384 protein assay. RESULTS: Two distinct endotypes of TC-PALF were identified, which differed in flow cytometry CD8+ Perforin1 (Prf) expression and liver biopsy staining of Prf. TC-PALF patients with high CD8+ Prf (TC-PALF High Prf) had monocytosis, with a unique circulating CD8 IFNγ+ Trm-like population and IFNγ-responsive CD14/CD16 monocyte ligand-receptor interaction. TC-PALF patients with normal CD8+ Prf expression had hypergammaglobulinemia, an increase in class-switched B-cells, and a decrease in serum inflammatory proteins associated with myeloid activation. CONCLUSIONS: TC-PALF high Prf patients have a unique circulating CD8+ IFNγ+ Trm-like population accompanied by monocyte proliferation and activation. Further understanding of the role of IFNγ in TC-PALF High Prf may provide a therapeutic target for this endotype to improve transplant-free survival.
Source: Hepatology Communications
Authors: Tamir Diamond, Catherine A. Chapin, Caroline J. Diorio, Sarah McCuaig, Michelle Lau, Niansheng Chu, Nora M. Gibson, Portia A. Kreiger, Simon Horslen, Kathleen M. Loomes, Anna M. Banc-Husu, Jaime Chu, M. Kyle Jensen, Daniel H. Leung, Amrita Narang, Beth A. Carter, Scott Elisofon, Ryan Fischer, Steven J. Lobritto, Mike Leonis, Anna L. Peters, Norberto Rodriguez-Baez, Rene Romero, Philip Rosenthal, David Rudnick, James Squires, Shikha Sundaram, Kyla M. Tolliver, Pamela Valentino, Valerie Durkalski, Estella M. Alonso, Edward M. Behrens
Institutions: Children's Hospital of Philadelphia, University of Pennsylvania, Northwestern University, Lurie Children's Hospital, University of Pittsburgh, Children's Hospital of Pittsburgh, Baylor College of Medicine, Texas Children's Hospital, Icahn School of Medicine at Mount Sinai, University of Utah, Lucile Packard Children's Hospital, University of Southern California, Children's Hospital of Los Angeles, Boston Children's Hospital, Children's Mercy Hospital, Columbia University, Cleveland Clinic, Cincinnati Children's Hospital Medical Center, The University of Texas Southwestern Medical Center, Emory University, Children's Healthcare of Atlanta, University of California, San Francisco, University of California San Francisco Medical Center, UCSF Benioff Children's Hospital, Washington University in St. Louis, Children's Hospital Colorado, University of Colorado Anschutz, Indiana University Hospital, Indiana University Indianapolis, Indiana University School of Medicine, Seattle Children's Hospital, University of Washington, Medical University of South Carolina
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,700
OpenAlex ID: W7147516511