Catherine A Chapin, Tamir Diamond, Joshua B Wechsler, Samantha L Gadd, Michelle Lau, Wenzhao Meng, Eline T Luning Prak, Jamie L Duke, Daria V Babushok, Kathleen M Loomes, Anat R Tambur, Estella M Alonso, Edward M Behrens
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.
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.