TCR β repertoire of memory T cell reveals potential role for Escherichia coli in the pathogenesis of primary biliary cholangitis

Background Primary biliary cholangitis ( PBC ) is an organ‐specific, T cell‐mediated autoimmune disease which is characterized by the breakdown of self‐tolerance to the highly conserved pyruvate dehydrogenase complex, especially the pyruvate dehydrogenase E2 complex ( PDC ‐E2). However, the molecular mechanism of breakdown of self‐tolerance is still unclear. Methods A combination of multiplex‐ PCR and immune repertoire sequencing ( IR ‐seq) was used for a standardized analysis of memory T cell receptor ( TCR ) β‐chain repertoire of PBC patient and healthy volunteers. In vitro induction and expansion of human PDC ‐E2 163‐176 (human PDC ‐E2)‐specific T cells and E coli PDC ‐E2 31‐44/134‐147/235‐248 ( E coli PDC ‐E2)‐specific T cells, and identified the human (and E coli ) PDC ‐E2‐specific TCR β repertoire by IR ‐seq. Results Primary biliary cholangitis patients have shorter complementarity‐determining region 3s ( CDR 3s), and higher degree of sequence overlap in the TCR β repertoire of memory T cell. Moreover, altered insertion patterns and skewed TRBV segment usage were observed in PBC patients. With regard to the pathogenesis, the concentration of E coli was higher in PBC patients’ faecal. The frequency of E coli (and human)‐specific TCR s was higher in the memory TCR β repertoire of PBC patients compared with healthy controls. Importantly, the TCR β repertoire characteristics were almost identical between E coli PDC ‐E2‐related TCR s and human PDC ‐E2‐related TCR s, including the patterns of TRBV usage, CDR 3 length and amino acid composition. Conclusion Our findings comprehensively revealed the TCR β repertoire characterization of PBC patients, and provided a TCR molecular basis to understand the mechanism of cross‐recognition between human PDC ‐E2 and E coli PDC ‐E2, and the imbalance of immune tolerance in PBC .