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

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. (H epatology 2016;63:1608‐1619)