Human γδ T Cell Receptor Repertoires in Peripheral Blood Remain Stable Despite Clearance of Persistent Hepatitis C Virus Infection by Direct-Acting Antiviral Drug Therapy.

Sarina Ravens,Christian Schultze-Florey,Katja Deterding,Verena Schlapphoff,Heiner Wedemeyer,Markus Cornberg,Akshay Dhingra,Immo Prinz,Julia Hengst,Christian Koenecke

doi:10.3389/fimmu.2018.00510

Sarina Ravens, Christian Schultze-Florey + Show 8 more

Open Access

https://doi.org/10.3389/fimmu.2018.00510

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Abstract

Human γδ T cells can contribute to clearance of hepatitis C virus (HCV) infection but also mediate liver inflammation. This study aimed to understand the clonal distribution of γδ T cells in peripheral blood of chronic HCV patients and following HCV clearance by interferon-free direct-acting antiviral drug therapies. To this end, γδ T cell receptor (TCR) repertoires were monitored by mRNA-based next-generation sequencing. While the percentage of Vγ9+ T cells was higher in patients with elevated liver enzymes and a few expanded Vδ3 clones could be identified in peripheral blood of 23 HCV-infected non-cirrhotic patients, overall clonality and complexity of γδ TCR repertoires were largely comparable to those of matched healthy donors. Monitoring eight chronic HCV patients before, during and up to 1 year after therapy revealed that direct-acting antiviral (DAA) drug therapies induced only minor alterations of TRG and TRD repertoires of Vγ9+ and Vγ9− cells. Together, we show that peripheral γδ TCR repertoires display a high stability (1) by chronic HCV infection in the absence of liver cirrhosis and (2) by HCV clearance in the course of DAA drug therapy.

Highlights

The majority of hepatitis C virus (HCV) infection results in chronicity and only 10–50% of cases are cleared in the acute phase [1, 2]
Flow cytometric analyses showed slightly decreased total γδ T cell frequencies, but a higher percentage of Vγ9+ T cells, in patients with higher ALT levels when compared with healthy controls (HC) and chronic HCV patients having low ALT levels (Figures 1A,B)
It was reasonable to expect an impact of chronic HCV infection and its clearance on γδ T cell dynamics, because γδ T cells play a role in the antiviral defense of CMV, HCV, and other viruses [22, 49, 50]

Summary

Introduction

The majority of hepatitis C virus (HCV) infection results in chronicity and only 10–50% of cases are cleared in the acute phase [1, 2]. The contribution of γδ T cells to HCV control is largely unknown. The random rearrangement of different gene segments creates a high clonal γδ-TCR Repertoires in Chronic HCV-Infection diversity, which is reflected in the junctional regions (CDR3 sequence) of TCR chains. The identity of molecules activating non-Vγ9JP+Vδ2+ cells is largely unknown. Non-Vγ9JP+Vδ2+ γδ T cells exert a high degree of antiviral and antitumor activity [15, 16], which is for instance reflected in the expansion of Vδ1+ γδ T cells in response to viral infection in immunocompromised patients, stem cell transplant recipients, and during pregnancy [17,18,19,20,21]

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