CD4⁺ T cells from patients with primary biliary cholangitis show T cell activation and differentially expressed T‐cell receptor repertoires

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 β‐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.

A Novel CCR7-Related Immune Prognostic Signature for Liver Hepatocellular Carcinoma (LIHC) Based on Immunogenomic Profiling

“…F2RL2 was reported associated with development of preneoplastic foci in liver and promote initiation of liver cancer [28]. TRBV10-3 was one of subtypes of TRBV10, which related to CD4 + T cells of primary biliary cholangitis patients [29]. The inactivation of SAMD9L was pointed contributes to progression of B virus-associated hepatocellular carcinoma via facilitation G1-S [30].…”

Isoform‐specific functions of Ras in T‐cell development and differentiation

“…Besides their role in oncogenesis, Ras-GTPases play an important role in cell migration and adhesion [19], parasitic [20], viral infections [21], and autoimmune disorders [3,4]. Ras-GTPase isoforms relay signals from the TCR regulating positive and negative selection, differentiation, and effector functions of T cells [14,16,[22][23][24] (Fig. 1).…”

“…RASopathies include the autoimmune lymphoproliferative syndrome caused by somatic mutation in N-Ras [26] and Rasassociated autoimmune leukoproliferative disease, causing recurrent infection and generalized lymphadenopathy [27]. As Ras is essential for T-helper subsets differentiation (Table 1) [28,29], Ras hyperactivation results in an abnormal effector T-cell repertoire [22]. Herein, we have assessed Ras isoforms' role in T-cell development, differentiation, and related diseases and raised critical issues in Ras-T-cell studies that need to be experimentally addressed.…”

An enhanced level of LAMP-2A participates in CD4+T cell hyperactivity in patients with primary biliary cholangitis

“…CD4 + T cells from patients with PBC show differential T cell receptor (TCR) repertoires and T cell activation (14), but the mechanism through which specific T cell subsets participate in the natural progression of the disease remains obscure (15,16). To address this issue, we designed the present study to evaluate the activation status of CD4 + T cells in PBC and to investigate the role of LAMP-2A in this process.…”