Hepatitis C virus-specific Th17 cells are suppressed by virus-induced TGF-beta

• Published in: The Journal of immunology (1950) 2008-10, Vol.181 (7), p.4485-4494
• Main Authors: Rowan, Aileen G, Fletcher, Jean M, Ryan, Elizabeth J, Moran, Barry, Hegarty, John E, O'Farrelly, Cliona, Mills, Kingston H G
• Format: Article
• Language: English
• Subjects: CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; Cell Proliferation; Cells, Cultured; Epitopes, T-Lymphocyte - immunology; Growth Inhibitors - biosynthesis; Growth Inhibitors - physiology; Hepacivirus - immunology; Hepatitis C, Chronic - immunology; Hepatitis C, Chronic - virology; Humans; Interleukin-10 - biosynthesis; Interleukin-10 - physiology; Interleukin-17 - biosynthesis; T-Lymphocytes, Helper-Inducer - cytology; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - virology; Th1 Cells - immunology; Th1 Cells - virology; Transforming Growth Factor beta - biosynthesis; Transforming Growth Factor beta - physiology; Viral Nonstructural Proteins - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.181.7.4485

IL-17-secreting T (Th17) cells play a protective role in certain bacterial infections, but they are major mediators of inflammation and are pathogenic in organ-specific autoimmune diseases. However, human Th17 cells appear to be resistant to suppression by CD4(+)CD25(+)FoxP3(+) regulatory T cells, suggesting that they may be regulated by alternative mechanisms. Herein we show that IL-10 and TGF-beta suppressed IL-17 production by anti-CD3-stimulated PBMC from normal individuals. TGF-beta also suppressed IL-17 production by purified CD4(+) T cells, whereas the inhibitory effect of IL-10 on IL-17 production appears to be mediated predominantly by its effect on APC. An examination of patients infected with hepatitis C virus (HCV) demonstrated that Ag-specific Th17 cells are induced during infection and that these cells are regulated by IL-10 and TGF-beta. PBMC from HCV Ab-positive donors secreted IL-17, IFN-gamma, IL-10, and TGF-beta in response to stimulation with the HCV nonstructural protein 4 (NS4). Furthermore, NS4 induced innate TGF-beta and IL-10 expression by monocytes from normal donors and at higher levels from HCV-infected patients. Neutralization of TGF-beta, and to a lesser extent IL-10, significantly enhanced NS4-specific IL-17 and IFN-gamma production by T cells from HCV-infected donors. Our findings suggest that both HCV-specific Th1 and Th17 cells are suppressed by NS4-induced production of the innate anti-inflammatory cytokines IL-10 and TGF-beta. This may represent a novel immune subversion mechanism by the virus to evade host-protective immune responses. Our findings also suggest that TGF-beta and IL-10 play important roles in constraining the function of Th17 cells in general.