Journal of pediatric gastroenterology and nutrition · 2026
Identification of human leukocyte antigen class I risk alleles and enriched T cell receptor groups in activated T cell pediatric acute liver failure.
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Chapin Catherine A, Diamond Tamir, Wechsler Joshua B, Gadd Samantha L, Lau Michelle, Meng Wenzhao, Luning Prak Eline T, Duke Jamie L, Babushok Daria V, Loomes Kathleen M, Tambur Anat R, Alonso Estella M, Behrens Edward M
Аннотация
OBJECTIVE: Activated T cell pediatric acute liver failure (TC-PALF) is characterized by CD8+T cells in liver and peripheral blood. TC-PALF patients are at increased risk of developing aplastic anemia (AA), an immune-mediated disorder in which CD8+ T cells target hematopoietic stem and progenitor cells. Clonal expansion of T cell receptors (TCRs) and specific human leukocyte antigen (HLA) class I risk alleles have been reported in AA. We hypothesized TC-PALF shares similar HLA associations and exhibits increased TCR clonality.
METHODS: Thirty-one TC-PALF and 15 other PALF diagnosis (other-PALF) patients enrolled in the Pediatric Acute Liver Failure Study Group (PALFSG) were included. Liver tissue DNA underwent TCR β-chain (TCRβ) complementarity-determining region 3 sequencing and HLA genotyping. HLA allele frequencies were compared with ethnicity-matched controls. TCR clonality was assessed and Grouping of Lymphocyte Interactions by Paratope Hotspots 2 (GLIPH2) was used to identify antigen-convergent, disease-associated TCR groups.
RESULTS: HLA class I alleles HLA-A*23:01, HLA-B*35:03, HLA-B*52:01, and HLA-B*39:05 were significantly overrepresented among TC-PALF patients compared to ethnicity-matched controls. Hepatic TCRβ clonality was increased in the TC-PALF group. GLIPH2 identified 158 statistically significant TCR convergence groups enriched in TC-PALF with significant HLA associations, representing putative antigen-specific TCR clusters.
CONCLUSIONS: Enrichment of specific HLA class I alleles, increased hepatic TCR clonality, and HLA-associated TCR convergence groups support an HLA-restricted, antigen-driven CD8+ T cell response as a central mechanism of TC-PALF. These findings provide a mechanistic framework for antigen discovery and future development of immunogenetic biomarkers to improve disease classification, risk stratification, and targeted immunomodulatory therapy.
METHODS: Thirty-one TC-PALF and 15 other PALF diagnosis (other-PALF) patients enrolled in the Pediatric Acute Liver Failure Study Group (PALFSG) were included. Liver tissue DNA underwent TCR β-chain (TCRβ) complementarity-determining region 3 sequencing and HLA genotyping. HLA allele frequencies were compared with ethnicity-matched controls. TCR clonality was assessed and Grouping of Lymphocyte Interactions by Paratope Hotspots 2 (GLIPH2) was used to identify antigen-convergent, disease-associated TCR groups.
RESULTS: HLA class I alleles HLA-A*23:01, HLA-B*35:03, HLA-B*52:01, and HLA-B*39:05 were significantly overrepresented among TC-PALF patients compared to ethnicity-matched controls. Hepatic TCRβ clonality was increased in the TC-PALF group. GLIPH2 identified 158 statistically significant TCR convergence groups enriched in TC-PALF with significant HLA associations, representing putative antigen-specific TCR clusters.
CONCLUSIONS: Enrichment of specific HLA class I alleles, increased hepatic TCR clonality, and HLA-associated TCR convergence groups support an HLA-restricted, antigen-driven CD8+ T cell response as a central mechanism of TC-PALF. These findings provide a mechanistic framework for antigen discovery and future development of immunogenetic biomarkers to improve disease classification, risk stratification, and targeted immunomodulatory therapy.