Dysregulated TFR and TFH cells correlate with B‐cell differentiation and antibody production in autoimmune hepatitis

Ma Liang,Zhang Liwen,Dai Juan,Chen Jianping,Ding Yanbo,Zhuang Yun

doi:10.1111/jcmm.14997

Ma Liang, Zhang Liwen + Show 4 more

Open Access

https://doi.org/10.1111/jcmm.14997

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Abstract

Follicular helper T (TFH) cell provides germinal centre (GC) B cell with critical signals for autoantibody production in the immunopathogenesis and progression of autoimmune hepatitis (AIH). However, the immunoregulatory functions of follicular regulatory T (TFR) cell in AIH are still unclear. The numbers of circulating TFR/TFH cells were measured in AIH patients. Moreover, we established experimental autoimmune hepatitis (EAH) model to examine the function of TFR cells on B‐cell differentiation and autoantibody production in vivo and vitro. AIH patients had significantly increased numbers of TFH cells and decreased numbers of TFR cells as well as imbalanced TFR/TFH‐type cytokines (IL‐10, TGF‐β1 and IL‐21) compared with healthy controls (HCs). In addition, TFR cell numbers negatively correlated with TFH cell numbers. Also, serum hypergammaglobulinaemia (IgG and IgM) concentration negatively correlated the levels of serum IL‐21, but positively correlated with the levels of serum IL‐10 in AIH patients. Furthermore, in comparison with control group, significantly higher frequencies of spleen TFR cells but lower frequencies of spleen TFH cells were detected in the EAH group. Further analysis found that TFR cells simultaneously express the phenotypic characteristics of Treg and TFH cells, but exercise as negative regulators of autoantibody production in vitro culture. Our findings demonstrated that dysregulated between TFR and TFH cells might cause excessive production of autoantibodies and destruction of the immune homeostasis, leading to the immunopathological process in AIH.

Highlights

Autoimmune hepatitis (AIH) is a severe progressive chronic autoimmune disease
We found that circulating TFH cells express higher levels of PD-1 and inducible T-cell co-stimulator (ICOS), and similar levels of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and CD25 in AIH patients compared with healthy controls (HCs)
This study showed sufficient evidence that dysregulated between TFR and TFH cells contribute to the immunopathological process in AIH

Summary

| INTRODUCTION

Autoimmune hepatitis (AIH) is a severe progressive chronic autoimmune disease. AIH is characterized by high levels of hypergammaglobulinaemia and hepatic inflammatory infiltrates, leading to potential cirrhosis.[1]. A newly identified T-cell subset, termed follicular regulatory T(TFR) cell, propose themselves as ideal candidates for preventing emergence of autoreactive B cells and regulating the normal GC response.[16,17] TFR cell combining phenotypic characteristics with conventional Foxp3+Tregs and TFH cell yet are not identical to both.[16,17,18] Similar to TFH cell, TFR cell migrates to the GC by expressing CXCR5, which is a chemokine receptor for CXCL13 Both subsets commonly express ICOS, PD-1 and Bcl6.16,17 Unlike TFH cell, which normally differentiate from naive CD4+T cell precursors, TFR cell originated from thymic Foxp3 + Treg precursors.[17] in comparison with TFH cell, TFR cell has unique characteristics by the expressions of Treg-related molecules.[18] Research confirmed that TFR cell simultaneously expresses the Treg master regulator Foxp[3] and other Treg-related molecules such as CD25 and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4).[16,17,18] Several studies have showed that abnormal TFR cells activity might cause the destruction of immune tolerance and thereby lead to the immunopathogenesis of autoimmune diseases.[19,20] like TFH cell, TFR cells are present in the peripheral circulation, the levels of which are directly correlated with a variety of human immunological disorders, such as primary biliary cholangitis (PBC) and multiple.

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Findings

| DISCUSSION