Blockade of virus infection by human CD4+ T cells via a cytokine relay network.
CD4(+) T cells directly participate in bacterial clearance through secretion of proinflammatory cytokines. Although viral clearance relies heavily on CD8(+) T cell functions, we sought to determine whether human CD4(+) T cells could also directly influence viral clearance through cytokine secretion. We found that IFN-gamma and TNF-alpha, secreted by IL-12-polarized Th1 cells, displayed potent antiviral effects against a variety of viruses. IFN-gamma and TNF-alpha acted directly to inhibit hepatitis C virus replication in an in vitro replicon system, and neutralization of both cytokines was required to block the antiviral activity that was secreted by Th1 cells. IFN-gamma and TNF-alpha also exerted antiviral effects against vesicular stomatitis virus infection, but in this case, functional type I IFN receptor activity was required. Thus, in cases of vesicular stomatitis virus infection, the combination of IFN-gamma and TNF-alpha secreted by human Th1 cells acted indirectly through the IFN-alpha/beta receptor. These results highlight the importance of CD4(+) T cells in directly regulating antiviral responses through proinflammatory cytokines acting in both a direct and indirect manner.
Davis
Ann M
AM
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9093, USA.
Hagan
Kristan A
KA
Matthews
Loderick A
LA
Bajwa
Gagan
G
Gill
Michelle A
MA
Gale
Michael
M
Farrar
J David
JD
D015153:Blotting, Western; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D016174:Hepacivirus / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology*; D014777:Virus Diseases / Q000276:immunology*; D014779:Virus Replication
D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma