CD8 TRM-like T cells expressing perforin and IFN-γ define a pediatric activated T-cell acute liver failure endotype

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.

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Journal
Hepatology Communications
Published
2026-03-31
DOI
https://doi.org/10.1097/hc9.0000000000000926
Primary Topic
Drug-Induced Hepatotoxicity and Protection
Type
article
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article

CD8 TRM-like T cells expressing perforin and IFN-γ define a pediatric activated T-cell acute liver failure endotype

Nora M. Gibson, Michelle Lau, Pamela L. Valentino, Anna L. Peters et al.
Hepatology Communications
Drug-Induced Hepatotoxicity and Protection
article

CD8 TRM-like T cells expressing perforin and IFN-γ define a pediatric activated T-cell acute liver failure endotype

Nora M. Gibson, Michelle Lau, Pamela L. Valentino, Anna L. Peters, David A. Rudnick, Estella M. Alonso, Beth A. Carter, Ryan T. Fischer, Steven Lobritto, Simon Horslen, Jaime Chu, Mike A. Leonis, Shikha S. Sundaram, James E. Squires, Kathleen M. Loomes, Niansheng Chu, Scott A. Elisofon, René Romero, Amrita Narang, Catherine A. Chapin, Tamir Diamond, Kyla M. Tolliver, Portia A. Kreiger, Daniel H. Leung, M. Kyle Jensen, Anna M. Banc-Husu, Norberto Rodriguez-Baez, Edward M. Behrens, Valerie Durkalski, Caroline J. Diorio, Sarah McCuaig, Philip Rosenthal
article en

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.

Hepatology CommunicationsVol. 10(4)
Northwestern University (US), Cincinnati Children's Hospital Medical Center (US), Boston Children's Hospital (US), Cleveland Clinic (US), Children's Mercy Hospital (US), Lucile Packard Children's Hospital (US), Children's Hospital of Philadelphia (US), Children's Hospital of Los Angeles (US), Medical University of South Carolina (US), Baylor College of Medicine (US), Washington University in St. Louis (US), University of Utah (US), Children's Hospital Colorado (US), Seattle Children's Hospital (US), Lurie Children's Hospital (US), Children's Hospital of Pittsburgh (US), UCSF Benioff Children's Hospital (US), Children's Healthcare of Atlanta (US), Texas Children's Hospital (US), Indiana University School of Medicine, Indiana University – Purdue University Indianapolis (US), Columbia University (US), The University of Texas Southwestern Medical Center (US), University of Colorado Denver (US), Icahn School of Medicine at Mount Sinai (US)
University of Pennsylvania
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Openalex Percentile: Top 35%
Drug-Induced Hepatotoxicity and Protection
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