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 4

Functional analysis of HCV-specific CD4+ T cells.

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Functional analysis of HCV-specific CD4+ T cells. (A) Representative flo...
(A) Representative flow cytometry plots for Th1 cytokine secretion by HCV-specific CD4+ T cells after stimulation with HCV proteins. Antigen-specific CD4 responses were identified as CD40L+CD4+ T cells. (B) Higher frequency of CD40L+ expressing CD4+ T cells (of total CD4+ cells) in response to HCV protein stimulation in 13 patients with resolving versus 9 with progressing infections (P = 0.016, 2-tailed Mann-Whitney U test). (C) (Poly)functional profiles of the CD40L-expressing cells. Progressors, red; resolvers, blue. (D) The mean number of CD40L+ CD4 populations secreting 0, 1, 2, or 3 cytokines. Representative flow cytometry plot demonstrating detection of tetramer-positive CD4+ T cells directly ex vivo and proliferation capacity of these cells upon cognate peptide stimulation in the absence or presence of rIL-2. After 14 days of culture, proliferating antigen-specific CD4+ T cells were identified as CD3+CD4+ Class II tetramer+ CellTrace Far Red by flow cytometry. Expression levels of PD-1 (E) and CTLA-4 (F) in samples that proliferated versus those that did not in the absence of rIL-2 (***P < 0.001, 2-tailed Mann-Whitney U test).