High-throughput T-cell receptor sequencing across chronic liver diseases reveals distinct disease-associated repertoires

Hepatology. 2016 May;63(5):1608-19. doi: 10.1002/hep.28116. Epub 2015 Sep 30.


Hepatic T-cell infiltrates and a strong genetic human leukocyte antigen association represent characteristic features of various immune-mediated liver diseases. Conceptually the presence of disease-associated antigens is predicted to be reflected in T-cell receptor (TCR) repertoires. Here, we aimed to determine if disease-associated TCRs could be identified in the nonviral chronic liver diseases primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and alcoholic liver disease (ALD). We performed high-throughput sequencing of the TCRβ chain complementarity-determining region 3 of liver-infiltrating T cells from PSC (n = 20), PBC (n = 10), and ALD (n = 10) patients, alongside genomic human leukocyte antigen typing. The frequency of TCRβ nucleotide sequences was significantly higher in PSC samples (2.53 ± 0.80, mean ± standard error of the mean) compared to PBC samples (1.13 ± 0.17, P < 0.0001) and ALD samples (0.62 ± 0.10, P < 0.0001). An average clonotype overlap of 0.85% was detected among PSC samples, significantly higher compared to the average overlap of 0.77% seen within the PBC (P = 0.024) and ALD groups (0.40%, P < 0.0001). From eight to 42 clonotypes were uniquely detected in each of the three disease groups (≥30% of the respective patient samples). Multiple, unique sequences using different variable family genes encoded the same amino acid clonotypes, providing additional support for antigen-driven selection. In PSC and PBC, disease-associated clonotypes were detected among patients with human leukocyte antigen susceptibility alleles.

Conclusion: We demonstrate liver-infiltrating disease-associated clonotypes in all three diseases evaluated, and evidence for antigen-driven clonal expansions. Our findings indicate that differential TCR signatures, as determined by high-throughput sequencing, may represent an imprint of distinctive antigenic repertoires present in the different chronic liver diseases; this thereby opens up the prospect of studying disease-relevant T cells in order to better understand and treat liver disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cholangitis, Sclerosing / immunology*
  • Chronic Disease
  • Female
  • Genes, T-Cell Receptor beta
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Liver Cirrhosis, Biliary / immunology*
  • Liver Diseases, Alcoholic / immunology*
  • Male
  • Middle Aged
  • Receptors, Antigen, T-Cell, alpha-beta / genetics*


  • Receptors, Antigen, T-Cell, alpha-beta