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Blockade of Virus Infection by Human CD4⁺ T Cells via a Cytokine Relay Network¹

Ann M. Davis^*, Kristan A. Hagan, Loderick A. Matthews^*, Gagan Bajwa, Michelle A. Gill, Michael Gale, Jr. and J. David Farrar^2,*,

^* Department of Immunology, Department of Molecular Biology, and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390; and Department of Immunology, University of Washington, Seattle, WA 98195

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- and TNF-, secreted by IL-12-polarized Th1 cells, displayed potent antiviral effects against a variety of viruses. IFN- and TNF- 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- and TNF- 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- and TNF- secreted by human Th1 cells acted indirectly through the IFN-/β 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.

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 study was supported by the following grants from the National Institutes of Health/National Institute of Allergy and Infectious Diseases: AI060389 and AI40035 awarded to M.G., and AI056222 awarded to J.D.F. A.M.D. was supported by a training grant from the National Institutes of Health/GM (GM00820317).

² Address correspondence and reprint requests to Dr. J. David Farrar, Department of Immunology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9093. E-mail address: David.Farrar{at}UTSouthwestern.edu

³ Abbreviations used in this paper: ISG, IFN-sensitive gene; cDMEM, complete DMEM; cIMDM, complete IMDM; HCV, hepatitis C virus; IFNAR, IFN-/β receptor; LT, lymphotoxin; rh, recombinant human; RSV, respiratory syncytial virus; VSV, vesicular stomatitis virus.