Hepatitis C virus-specific Th17 cells are suppressed by virus-induced TGF-beta.
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.
Rowan
Aileen G
AG
School of Biochemistry and Immunology, Trinity College Dublin, Ireland.
Fletcher
Jean M
JM
Ryan
Elizabeth J
EJ
Moran
Barry
B
Hegarty
John E
JE
O'Farrelly
Cliona
C
Mills
Kingston H G
KH
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000821:virology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000502:physiology*; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology / Q000821:virology; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000502:physiology; D020381:Interleukin-17 / Q000096:biosynthesis*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology* / Q000821:virology; D018417:Th1 Cells / Q000276:immunology / Q000821:virology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000502:physiology*; D017361:Viral Nonstructural Proteins / Q000502:physiology
D018984:Epitopes, T-Lymphocyte; D006131:Growth Inhibitors; D020381:Interleukin-17; C093542:NS4 protein, hepatitis C virus; D016212:Transforming Growth Factor beta; D017361:Viral Nonstructural Proteins; D016753:Interleukin-10