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* School of Biochemistry and Immunology, Trinity College Dublin, and
National Liver Transplant Unit, St. Vincent’s University Hospital, Dublin, Ireland
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-β suppressed IL-17 production by anti-CD3-stimulated PBMC from normal individuals. TGF-β 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-β. PBMC from HCV Ab-positive donors secreted IL-17, IFN-
, IL-10, and TGF-β in response to stimulation with the HCV nonstructural protein 4 (NS4). Furthermore, NS4 induced innate TGF-β and IL-10 expression by monocytes from normal donors and at higher levels from HCV-infected patients. Neutralization of TGF-β, and to a lesser extent IL-10, significantly enhanced NS4-specific IL-17 and IFN- 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-β. This may represent a novel immune subversion mechanism by the virus to evade host-protective immune responses. Our findings also suggest that TGF-β and IL-10 play important roles in constraining the function of Th17 cells in general.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Irish Health Research Board and by Science Foundation Ireland.
2 Current address: Department of Immunology, Wright-Fleming Building, Faculty of Medicine, St. Mary’s Campus, Imperial College, Norfolk Place, London W5 1PG, UK.
3 Address correspondence and reprint requests to Dr. Kingston H. G. Mills, School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland. E-mail address: kingston.mills{at}tcd.ie
4 Abbreviations used in this paper: Th17 cell, IL-17-secreting CD4+ T cell; HCV, hepatitis C virus; LAP, latency-associated peptide; NS4, non-structural protein 4; Treg cell, regulatory T cell.
This article has been cited by other articles:
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  K. Gutkowski and M. Hartleb Comment on "Hepatitis C Virus-Specific Th17 Cells Are Suppressed by Virus-Induced TGF-{beta}" J. Immunol., May 15, 2009; 182(10): 5889 - 5889. [Full Text] [PDF]
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K. H. G. Mills, A. G. Rowan, and J. M. Fletcher Response to Comment on "Hepatitis C Virus-Specific Th17 Cells Are Suppressed by Virus-Induced TGF-{beta}" J. Immunol., May 15, 2009; 182(10): 5889 - 5890. [Full Text] [PDF]
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