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

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 1

Frequencies of HCV-specific CD4+ T cells over time and inhibitory receptor expression on HCV-specific CD4+ versus CD8+ T cells.

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Frequencies of HCV-specific CD4+ T cells over time and inhibitory recept...
(A) HCV-specific CD4+ T cell frequencies from longitudinally sampled PBMCs of 33 patient progressors (top) and 22 resolvers (bottom). At least one HCV-specific CD4 response was detected in 27 of 33 (81%) progressors and 22 of 22 (100%) resolvers during the earliest phase of infection. However, HCV-specific CD4+ T cells quickly disappeared in blood of progressors, whereas a small population of these cells remained detectable directly ex vivo in resolvers years after resolution of infection. (B) Representative flow contour plots demonstrating expression of inhibitory receptors on HCV-specific CD4+ (top) or CD8+ T cells (bottom). (C) Cumulative data of the percentages of HCV-specific CD4+ and CD8+ T cells expressing each indicated inhibitory receptor. CD4+ T cell inhibitory receptor phenotypes were analyzed from a total of 15 progressors and 8 resolvers, while HCV-specific CD8+ T cells were examined from a total of 11 progressors and 8 resolvers. Each patient was analyzed at 2 to 3 time points.