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Cutting Edge: Murine Cytomegalovirus Induces a Polyfunctional CD4 T Cell Response¹

Ramon Arens^*, Peng Wang, John Sidney, Andrea Loewendorf, Alessandro Sette, Stephen P. Schoenberger^*, Bjoern Peters^2, and Chris A. Benedict^2,

^* Division of Developmental Immunology, Division of Vaccine Discovery, and Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037

CD4 T lymphocytes regulate the adaptive immune response to most viruses, both by providing help to CD8 T cells and B cells as well as through direct antiviral activity. Currently, no mouse cytomegalovirus (MCMV)-specific CD4 T cell responses are known. In this study, we identify and characterize 15 I-A^b-restricted CD4 T cell responses specific for MCMV epitopes. CD4 T cells accumulate to high levels in the spleen and lungs during acute infection and produce multiple cytokines (IFN-, TNF, IL-2, IL-10, and IL-17). Interestingly, IL-17 and IFN- production within epitope-specific cells was found to be mutually exclusive. CD4 T cells recognizing a peptide derived from m09 were only detectable at later times of infection and displayed a unique cytokine production profile. In total, this study reveals that the MCMV-specific CD4 T cell response is complex and functionally diverse, highlighting its important role in controlling this persistent pathogen.

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 in part by a Veni Grant from The Netherlands Organization for Scientific Research (to R.A.), National Institutes of Health (NIH) Grants AI048073 and AI057840, NIH Contract HHSN26620040006C, Pacific Southwest Regional Center of Excellence Grant U54AI065359, and NIH Contract N01-AI-40023 (to A.S. and B.P.), Deutsche Forschungsgemeinschaft (DFG) fellowship (to A.L.), and NIH Grants CA081261 and AI076972 (to S.P.S.).

² Address correspondence and reprint requests to Dr. Chris A. Benedict (communicating author for editorial and production offices), Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail address: benedict{at}liai.org or Dr. Bjoern Peters, Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail address: bpeters{at}liai.org

³ Abbreviations used in this paper: MCMV, mouse CMV; IE, immediate early; ORF, open reading frame.