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Dendritic Cells Present Lytic Antigens and Maintain Function throughout Persistent -Herpesvirus Infection¹

Fiona Kupresanin^*, Jonathan Chow^2,*, Adele Mount^*, Christopher M. Smith, Philip G. Stevenson and Gabrielle T. Belz^3,*

^* The Walter and Eliza Hall Institute of Medical, Melbourne, Victoria, Australia; and Virology, Department of Pathology, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United Kingdom

The activation and maintenance of Ag-specific CD8⁺ T cells is central to the long-term control of persistent infections. These killer T cells act to continuously scan and remove reservoirs of pathogen that have eluded the acute immune response. Acutely cleared viral infections depend almost exclusively on dendritic cells (DC) to present Ags to, and to activate, the CD8⁺ T cell response. Paradoxically, persistent pathogens often infect professional APCs such as DC, in addition to infecting a broad range of nonprofessional APC, raising the possibility that many cell types could present viral Ags and activate T cells. We addressed whether in persistent viral infection with murine gammaherpesviruses, DC or non-DC, such as B cells and macrophages, were required to maintain the continued activation of Ag-specific CD8⁺ T cells. We found that presentation of the surrogate Ag, OVA, expressed under a lytic promoter to CD8⁺ T cells during persistent infection was largely restricted to DC, with little contribution from other lymphoid resident cells, such as B cells. This is despite the fact that B cells harbor a very large reservoir of latent virus. Our results support that, during persistent viral infection, continual presentation of lytic Ags by DC leads to T cell activation critical for maintaining CD8⁺ T cells capable of limiting persistent viral infection.

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 funded by the National Health and Medical Research Council (NHMRC) of Australia, a University of Melbourne Research Scholarship (to A.M. and C.M.S.), and an NHMRC C.J. Martin Fellowship (to C.M.S), a Harvard College and Howard Hughes Medical Institute Scholarship (to J.C), a Wellcome Trust Senior Overseas Fellowship (to G.T.B.), and Howard Hughes Medical Institute International Fellowship (to G.T.B.).

² Current address: Harvard College, Cambridge, MA 02138, E-mail address: chow2{at}fas.harvard.edu

³ Address correspondence and reprint requests to Dr. Gabrielle T. Belz, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria, 3050, Australia. E-mail address: belz{at}wehi.edu.au

⁴ Abbreviations used in this paper: DC, dendritic cell; -HV, gammaherpesviruses; MHV-68, murine -HV 68; LCMV, lymphocytic choriomeningitis viral; PFU, plaque-forming units; ORF, open reading frame; DTR, diptheria toxin receptor; DN, double negative.