Inhibitory Molecules That Regulate Expansion and Restoration of HCV-Specific CD4 + T Cells in Patients With Chronic Infection

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 141; no. 4; pp. 1422 - 1431.e6
• Main Authors: Raziorrouh, Bijan, Ulsenheimer, Axel, Schraut, Winfried, Heeg, Malte, Kurktschiev, Peter, Zachoval, Reinhart, Jung, Maria–Christina, Thimme, Robert, Neumann–Haefelin, Christoph, Horster, Sophia, Wächtler, Martin, Spannagl, Michael, Haas, Jürgen, Diepolder, Helmut M., Grüner, Norbert H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2011
• Subjects: Antibodies, Neutralizing; Antigens, CD - immunology; Antigens, CD - metabolism; Antigens, Surface - metabolism; Antiviral Response; Case-Control Studies; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; Cell Proliferation; Cells, Cultured; CTLA-4 Antigen - metabolism; Female; Gastroenterology and Hepatology; Germany; Hepacivirus - genetics; Hepacivirus - immunology; Hepatitis C, Chronic - diagnosis; Hepatitis C, Chronic - immunology; Herpesvirus 4, Human - immunology; Humans; IFN-γ; Immune Regulation; Interferon-gamma - metabolism; Interleukin-10 - immunology; Interleukin-10 - metabolism; Interleukin-2 - metabolism; Lymphocyte Activation; Male; Middle Aged; Orthomyxoviridae - immunology; Programmed Cell Death 1 Receptor - metabolism; Receptors, Cell Surface - metabolism; RNA, Viral - blood; TNF; Transforming Growth Factor beta1 - immunology; Transforming Growth Factor beta1 - metabolism; Tumor Necrosis Factor-alpha - metabolism; Viral Load; Germany; IL; MHC; FACS; Antiviral Response; TNF; PBMC; IFN; MFI; IFN-γ; TGF; HIV; cHCV; Immune Regulation; EBV; CTLA-4; PD-1; fluorescence-activated cell sorting; major histocompatibility complex; mean fluorescent intensity; cytotoxic T lymphocyte–associated antigen 4; interleukin; Epstein–Barr virus; interferon; tumor necrosis factor; programmed death 1; human immunodeficiency virus; transforming growth factor; chronic hepatitis C virus; peripheral blood mononuclear cell
• ISSN: 0016-5085; 1528-0012; 1528-0012
• DOI: 10.1053/j.gastro.2011.07.004

Inhibitory receptors such as programmed death 1 (PD-1) and cytotoxic T lymphocyte–associated antigen (CTLA)-4 mediate CD8 + T-cell exhaustion during chronic viral infection, but little is known about roles in dysfunction of CD4 + T cells. We investigated the functions of inhibitory molecules on hepatitis C virus (HCV)-, influenza-, and Epstein–Barr virus (EBV)-specific CD4 + T cells in patients with chronic infections compared with patients with resolved HCV infection and healthy donors. Expression of PD-1, CTLA-4, CD305, and CD200R were analyzed on HCV-specific CD4 + T cells, isolated from peripheral blood using major histocompatibility complex class II tetramers. We investigated the effects of in vitro inhibition of various inhibitory pathways on proliferation and cytokine production by CD4 + T cells, and we compared these effects with those from inhibition of interleukin (IL)-10 and transforming growth factor (TGF)-β1. PD-1 and CTLA-4 were up-regulated on virus-specific CD4 + T cells from patients with chronic HCV infections. PD-1 expression was lower on influenza- than on HCV-specific CD4 + T cells from subjects with chronic HCV infection, whereas CTLA-4 was expressed at similar levels, independent of their specificity. CD305 and CD200R were up-regulated in HCV resolvers. Blockade of PD-L1/2, IL-10, and TGF-β1 increased expansion of CD4 + T cells in patients with chronic HCV, whereas inhibition of IL-10 and TGF-β1 was most effective in restoring HCV-specific production of interferon gamma, IL-2, and tumor necrosis factor α. We characterized expression of inhibitory molecules on HCV-, influenza-, and EBV-specific CD4 + T cells and the effects of in vitro blockade on CD4 + T-cell expansion and cytokine production. Inhibition of PD-1, IL-10, and TGF-β1 is most efficient in restoration of HCV-specific CD4 + T cells.