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

Abstract

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‐E2163‐176 (human PDC‐E2)‐specific T cells and E coli PDC‐E231‐44/134‐147/235‐248 (E coli PDC‐E2)‐specific T cells, and identified the human (and E coli) PDC‐E2‐specific TCRβ repertoire by IR‐seq. Results Primary biliary cholangitis patients have shorter complementarity‐determining region 3s (CDR3s), and higher degree of sequence overlap in the TCRβ 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 TCRs was higher in the memory TCRβ repertoire of PBC patients compared with healthy controls. Importantly, the TCRβ repertoire characteristics were almost identical between E coli PDC‐E2‐related TCRs and human PDC‐E2‐related TCRs, including the patterns of TRBV usage, CDR3 length and amino acid composition. Conclusion Our findings comprehensively revealed the TCRβ 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.

Serotonin: A Potent Immune Cell Modulator in Autoimmune Diseases

“…In the early stage of PBC, NK cell killing activity is enhanced, and monocytes and macrophages have a high response to pathogen-associated antigens (66). Then, Th1 cells and cytotoxic T lymphocyte are activated (67,68). Furthermore, autoreactive B cells secrete large amount of antimitochondrial antibodies (69).…”

Identifying Hepatocellular Carcinoma Driver Genes by Integrative Pathway Crosstalk and Protein Interaction Network

“…We selected the top 20 items of GO with the lowest p value to show in the Figure 2A. Among them, some GO terms were previously studied to be associated with the pathogenesis of HCC and liver disease, such as cytokine activity (Diao et al , 2012), RNA polymerase II transcription factor binding (Stefanska et al , 2013), signal transducer, downstream of receptor, with serine/threonine kinase activity (Hou et al , 2019), and mitogen-activated protein kinase binding (Yang et al , 2014). These results were consistent with the finding that complicated connections exist within the mechanism of HCC.…”

Preselection TCR repertoire predicts CD4+ and CD8+ T‐cell differentiation state

“…CD4 + naive and CD4 + memory cells were defined as CD4 + CD8 − CD45RA + CD45RO − and CD4 + CD8 − CD45RA − CD45RO + , respectively. CD8 + naive and CD8 + memory cells were defined as CD4 − CD8 + CD45RA + CD45RA − and CD4 − CD8 + CD45RA − CD45RO + , respectively 9 . The number of each T‐cell subset isolated from each donor is shown in Table .…”

“…CD8 + naive and CD8 + memory cells were defined as CD4 À CD8 + CD45RA + CD45RA À and CD4 À CD8 + CD45RA À CD45RO + , respectively. 9 The number of each T-cell subset isolated from each donor is shown in Table S1. Flow cytometry (FACS) analysis confirmed that all sorted populations contained more than 500 000 cells and > 95% pure.…”