CD4+ T cells from patients with primary biliary cholangitis show T cell activation and differentially expressed T-cell receptor repertoires.
Hepatol Res
; 49(6): 653-662, 2019 Jun.
Article
em En
| MEDLINE
| ID: mdl-30690835
ABSTRACT
AIM:
Primary biliary cholangitis (PBC) is an autoimmune liver disease with unknown pathogenesis. In PBC, activation of T-cell receptor (TCR) signaling is associated with inflammatory cytokine production through N-Ras upregulation. Although the CD4+ T cell TCR repertoire could be associated with PBC pathogenesis, it has not been evaluated. Thus, we analyzed the PBC-CD4+ T cell TCR repertoire using next generation sequencing (NGS).METHODS:
Four PBC patients (one treatment-naïve and three receiving ursodeoxycholic acid) and three healthy individuals were enrolled. NRAS expression in CD4+ T cells was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). N-Ras dynamics in CD4+ T cells were assessed by qRT-PCR and GTP-N-Ras activation assay. The TCR α- (TRA) and ß-chain (TRB) repertoires on CD4+ T cells were analyzed by NGS and profiled using hierarchical analysis. Motif analysis was undertaken to elucidate the structure of PBC-specific TCRs.RESULTS:
NRAS was upregulated in PBC relative to control CD4+ T cells (P < 0.05), and N-Ras enhanced T cell activation in CD4+ T cells. Among 2668 TRAs and 841 TRBs, 20 and 11, respectively, were differentially expressed in PBC compared to that in controls (P < 0.05, fold-change >2). Among them, TRAV29/J22, TRBV6-5/J2-6, and TRBV10-1/J2-1 were expressed in PBC but the expression was negligible in the controls, with more mature and longer forms observed in PBC-CD4+ T cells.CONCLUSIONS:
N-Ras was upregulated in PBC-CD4+ T cells, and it enhanced TCR activation, indicating that PBC-CD4+ T cells were activated by N-Ras upregulation with differentially expressed TCR repertoires on their surfaces.
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MEDLINE
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article