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Hepatitis C virus–specific CD4+ T cell phenotype and function in different infection outcomes
Diana Y. Chen, … , Lia Lewis-Ximenez, Georg M. Lauer
Diana Y. Chen, … , Lia Lewis-Ximenez, Georg M. Lauer
Published January 6, 2020
Citation Information: J Clin Invest. 2020;130(2):768-773. https://doi.org/10.1172/JCI126277.
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Concise Communication Immunology Infectious disease

Hepatitis C virus–specific CD4+ T cell phenotype and function in different infection outcomes

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Abstract

CD4+ T cell failure is a hallmark of chronic hepatitis C virus (HCV) infection. However, the mechanisms underlying the impairment and loss of virus-specific CD4+ T cells in persisting HCV infection remain unclear. Here we examined HCV-specific CD4+ T cells longitudinally during acute infection with different infection outcomes. We found that HCV-specific CD4+ T cells are characterized by expression of a narrower range of T cell inhibitory receptors compared with CD8+ T cells, with initially high expression levels of PD-1 and CTLA-4 that were associated with negative regulation of proliferation in all patients, irrespective of outcome. In addition, HCV-specific CD4+ T cells were phenotypically similar during early resolving and persistent infection and secreted similar levels of cytokines. However, upon viral control, CD4+ T cells quickly downregulated inhibitory receptors and differentiated into long-lived memory cells. In contrast, persisting viremia continued to drive T cell activation and PD-1 and CTLA-4 expression, and blocked T cell differentiation, until the cells quickly disappeared from the circulation. Our data support an important and physiological role for inhibitory receptor–mediated regulation of CD4+ T cells in early HCV infection, irrespective of outcome, with persistent HCV viremia leading to sustained upregulation of PD-1 and CTLA-4.

Authors

Diana Y. Chen, David Wolski, Jasneet Aneja, Lyndon Matsubara, Brandon Robilotti, Garrett Hauck, Paulo Sergio Fonseca de Sousa, Sonu Subudhi, Carlos Augusto Fernandes, Ruben C. Hoogeveen, Arthur Y. Kim, Lia Lewis-Ximenez, Georg M. Lauer

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Figure 2

HCV-specific CD4+ T cell phenotype during the initial 16 weeks of infection.

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HCV-specific CD4+ T cell phenotype during the initial 16 weeks of infect...
(A) Ex vivo phenotypic analysis of HCV-specific CD4+ T cells (dot plot) or total CD4+ T cells (contour plot) from the first available time point of resolvers and progressors. (B) Percentages of HCV-specific CD4+ T cells expressing each indicated immune markers are plotted for 10 progressors and 11 resolvers. No significant difference was found between the 2 groups of patients for any given marker. (C) PD-1 and CTLA-4 expression levels were also analyzed by median MFI. Statistical analysis was performed using the Kruskal-Wallis test.
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