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Analysis of HBV-Specific CD4 T-cell Responses and Identification of HLA-DR-Restricted CD4 T-Cell Epitopes Based on a Peptide Matrix
Published on: October 20, 2021
Hepatitis C virus-specific CD4+ T cell phenotype and function in different infection outcomes
Diana Y Chen1, David Wolski1, Jasneet Aneja1,2
1Gastrointestinal Unit and.
Insights
Hepatitis C virus (HCV) infection impairs CD4+ T cells. Persistent HCV drives T cell exhaustion via PD-1 and CTLA-4, leading to cell loss and hindering memory formation.
Area of Science:
- Immunology
- Virology
- Hepatology
Background:
- Chronic hepatitis C virus (HCV) infection is characterized by CD4+ T cell failure.
- Mechanisms of virus-specific CD4+ T cell impairment in persistent HCV remain unclear.
Purpose of the Study:
- To investigate the longitudinal behavior of HCV-specific CD4+ T cells during acute infection.
- To elucidate the role of inhibitory receptors in CD4+ T cell function and differentiation in HCV infection outcomes.
Main Methods:
- Longitudinal analysis of HCV-specific CD4+ T cells during acute infection.
- Assessment of T cell inhibitory receptor expression (PD-1, CTLA-4) and proliferation.
- Evaluation of cytokine secretion and memory cell differentiation.
Main Results:
- HCV-specific CD4+ T cells initially express high levels of PD-1 and CTLA-4, suppressing proliferation regardless of outcome.
- Phenotype and cytokine secretion are similar in early resolving and persistent infections.
- Viral control allows CD4+ T cell downregulation of inhibitory receptors and memory differentiation.
- Persistent viremia sustains PD-1 and CTLA-4 expression, blocking differentiation and leading to cell disappearance.
Conclusions:
- Inhibitory receptors play a physiological role in regulating CD4+ T cells during early HCV infection.
- Persistent HCV viremia drives sustained T cell exhaustion through PD-1 and CTLA-4, preventing effective immune memory.
- Understanding these mechanisms is crucial for developing strategies to restore CD4+ T cell function in chronic HCV.
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.
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