Hyperactive Follicular Helper T Cells Contribute to Dysregulated Humoral Immunity in Patients With Liver Cirrhosis.

Man Huang,Qing He,Zhenwen Liu,Jijing Shi,Mengmeng Qu,Xin Zhao,Hongbo Wang,Zhiwei Li,Juanjuan Zhao,Zheng Zhang,Shuye Zhang

doi:10.3389/fimmu.2019.01915

Abstract

Objectives: Liver cirrhosis (LC) is usually accompanied by cirrhosis associated immune dysfunction (CAID), including reduced naïve T cells and memory B cells. However, little is known regarding on follicular helper T (Tfh) cell compartments in cirrhotic patients, especially in the secondary lymphoid organs such as spleen. This study characterizes splenic Tfh cells and explores its association with humoral immunity and disease progression in cirrhotic patients.Methods: Using flow cytometry and histological staining, we analyzed the frequency and cytokine production of splenic Tfh cells from LC patients and healthy controls (HCs). Co-culture experiments of sorted Tfh and B cells were performed for functional analysis in vitro. The correlations between Tfh cells and disease progression markers as well as B cell subset perturbations were also examined.Results: PD-1highICOS+CXCR5+ Tfh cells were preferentially enriched in the spleen of cirrhotic patients, where they expressed higher levels of CXCR3 and produced more interleukin (IL)-21. Histologically, more splenic Tfh cells occupied the B cell follicular structure in LC patients where they shaped more active germinal centers (GCs) than those in HC spleens. In vitro, splenic Tfh cells in cirrhotic patients robustly induce plasma cell differentiation through IL-21 dependent manner. Finally, increased Tfh cell frequency is positively correlated with the plasma cells and disease severity in LC patients.Conclusions: We conclude that hyperactive Tfh cells contribute to dysregulated humoral immunity in patients with liver cirrhosis.

Highlights

Liver cirrhosis (LC) is the common outcome of liver inflammation induced by various etiologies such as hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol, drug, and fat [1]
We conclude that hyperactive Tfh cells contribute to dysregulated humoral immunity in patients with liver cirrhosis
These data partially define the characteristics of the cirrhosis associated immune dysfunction (CAID) in peripheral blood, but little is known about its impact on the secondary lymph organ (SLO) such as spleen of cirrhotic patients, especially for T cells and B cell compartments, the two most important arms in the adaptive immune system

Summary

Introduction

Liver cirrhosis (LC) is the common outcome of liver inflammation induced by various etiologies such as hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol, drug, and fat [1]. While LC impairs the liver physiological function, it causes cirrhosis associated immune dysfunction (CAID). The occurrence of CAID is associated with systemic inflammation during LC disease progression, which is reflected by the persistent activation of peripheral immune cells and the elevated serum pro-inflammatory cytokines [2, 4]. Circulating natural killer (NK) cells are compromised in liver cirrhosis and display poor responses to cytokine stimulation in vitro [11]. These data partially define the characteristics of the CAID in peripheral blood, but little is known about its impact on the secondary lymph organ (SLO) such as spleen of cirrhotic patients, especially for T cells and B cell compartments, the two most important arms in the adaptive immune system

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Conclusion