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West Nile Virus-Specific CD4 T Cells Exhibit Direct Antiviral Cytokine Secretion and Cytotoxicity and Are Sufficient for Antiviral Protection¹

James D. Brien^2,*, Jennifer L. Uhrlaub^*, and Janko Nikolich-ugich^3,*,

^* Vaccine and Gene Therapy Institute, Department of Molecular Microbiology and Immunology, and Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006; and Department of Immunobiology and Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ 85718

CD4 T cells have been shown to be necessary for the prevention of encephalitis during West Nile virus (WNV) infection. However, the mechanisms used by Ag-specific CD4 T cells to protect mice from WNV encephalitis remain incompletely understood. Contrary to the belief that CD4 T cells are protective because they merely maintain the CD8 T cell response and improve Ab production, in this study we provide evidence for the direct antiviral activity of CD4 T cells that functions to protect the host from WNV encephalitis. In adoptive transfers, naive CD4 T cells protected a significant number of lethally infected RAG^–/– mice, demonstrating the protective effect of CD4 T cells independent of B cells and CD8 T cells. To shed light on the mechanism of this protection, we defined the peptide specificities of the CD4 T cells responding to WNV infection in C57BL/6 (H-2^b) mice, and used these peptides to characterize the in vivo function of antiviral CD4 T cells. WNV-specific CD4 T cells produced IFN- and IL-2, but also showed potential for in vivo and ex vivo cytotoxicity. Furthermore, peptide vaccination using CD4 epitopes conferred protection against lethal WNV infection in immunocompetent mice. These results demonstrate the role of direct effector function of Ag-specific CD4 T cells in preventing severe WNV disease.

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 U.S. Public Health Service Awards N01 50027 (to J.N.-Z.), T32 AI007472 (to J.D.B.), and RR0163 (to the Oregon National Primate Research Center) from the National Institute of Allergy and Infectious Diseases and the National Institute for Research Resources, National Institutes of Health.

² Current address: Department of Microbiology, Washington University, 660 Euclid Avenue, St. Louis, MO 63110.

³ Address correspondence and reprint requests to Dr. Janko Nikolich-ugich, Department of Immunobiology, University of Arizona College of Medicine, P.O. Box 249221, 1501 North Campbell Avenue, Tucson, AZ 85724. E-mail address: nikolich{at}email.arizona.edu

⁴ Abbreviations used in this paper: WNV, West Nile virus; FCM, flow cytofluorometry; GzB, granzyme B; ICCS, intracellular cytokine staining; JEV, Japanese encephalitis virus; NS3, nonstructural protein 3.

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