Follicular T helper cells shape the HCV-specific CD4+ T cell repertoire after virus elimination
Maike Smits, … , Robert Thimme, Tobias Boettler
Maike Smits, … , Robert Thimme, Tobias Boettler
Published November 7, 2019
Citation Information: J Clin Invest. 2020;130(2):998-1009. https://doi.org/10.1172/JCI129642.
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Clinical Research and Public Health Immunology Infectious disease

Follicular T helper cells shape the HCV-specific CD4+ T cell repertoire after virus elimination

Abstract

BACKGROUND Chronic hepatitis C virus (HCV) infection is characterized by a severe impairment of HCV-specific CD4+ T cell help that is driven by chronic antigen stimulation. We aimed to study the fate of HCV-specific CD4+ T cells after virus elimination.METHODS HCV-specific CD4+ T cell responses were longitudinally analyzed using MHC class II tetramer technology, multicolor flow cytometry, and RNA sequencing in a cohort of patients chronically infected with HCV undergoing therapy with direct-acting antivirals. In addition, HCV-specific neutralizing antibodies and CXCL13 levels were analyzed.RESULTS We observed that the frequency of HCV-specific CD4+ T cells increased within 2 weeks after initiating direct-acting antiviral therapy. Multicolor flow cytometry revealed a downregulation of exhaustion and activation markers and an upregulation of memory-associated markers. Although cells with a Th1 phenotype were the predominant subset at baseline, cells with phenotypic and transcriptional characteristics of follicular T helper cells increasingly shaped the circulating HCV-specific CD4+ T cell repertoire, suggesting antigen-independent survival of this subset. These changes were accompanied by a decline of HCV-specific neutralizing antibodies and the germinal center activity.CONCLUSION We identified a population of HCV-specific CD4+ T cells with a follicular T helper cell signature that is maintained after therapy-induced elimination of persistent infection and may constitute an important target population for vaccination efforts to prevent reinfection and immunotherapeutic approaches for persistent viral infections.FUNDING Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), the National Institute of Allergy and Infectious Diseases (NIAID), the European Union, the Berta-Ottenstein-Programme for Advanced Clinician Scientists, and the ANRS.

Authors

Maike Smits, Katharina Zoldan, Naveed Ishaque, Zuguang Gu, Katharina Jechow, Dominik Wieland, Christian Conrad, Roland Eils, Catherine Fauvelle, Thomas F. Baumert, Florian Emmerich, Bertram Bengsch, Christoph Neumann-Haefelin, Maike Hofmann, Robert Thimme, Tobias Boettler

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Figure 3

Longitudinal analysis of inhibitory receptors and activation markers on HCV-specific CD4+ T cells during antiviral therapy.

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Longitudinal analysis of inhibitory receptors and activation markers on ...
(A and C–I) Expression of different inhibitory receptors and activation markers on HCV-specific CD4+ T cells was assessed at the indicated time points before and during antiviral therapy. Median expression of the individual surface marker on HCV-specific CD4+ T cells is characterized by the blue dots and lines. The MFI of the individual samples and the median MFI are displayed as white scattered dots and green bars, respectively (n = 20 for PD-1, OX40, and ICOS; n = 10 for BTLA, CD38, CD305, TIGIT, and CD38). Each symbol represents 1 patient, bars represent medians. (B and J) Representative pseudocolor plots for expression of PD-1 and ICOS on HCV-specific CD4+ T cells from 2 patients (P3 and P19) are shown after gating on live, non-naive CD4+ T cells. **P < 0.01, ***P < 0.001, ****P < 0.0001; nonparametric distribution with Wilcoxon’s matched-pairs signed-rank test between indicated groups. Due to multiple comparisons (n = 3), significance level was adjusted using Bonferroni’s correction and P values of < 0.01 were considered statistically significant. Thus, P values > 0.01 are not indicated.