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* Complex Systems in Biology Group, Centre for Vascular Research, University of New South Wales, Kensington, Australia;
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545;
Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia; and
Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
Ag presentation within the regional lymph node is crucial for the initiation of CD8+ T cell responses following viral infection. The magnitude and quality of the CD8+ T cell response are regulated by the interplay between the size of the APC population and duration of Ag presentation. To understand how these parameters are finely regulated during an immune response, we have investigated the dynamics of Ag presentation in influenza A virus and HSV-1 infection. In both infections, APC production was calculated to occur over the first few days of infection, after which there was slow exponential decay over a period of up to 2 wk. This production rate is most likely determined by the Ag availability and recruitment and/or maturation rate of dendritic cells. APC production was found to closely parallel lymph node cell recruitment in both infections. This was greatest in the first 6 h of infection for HSV and over the second and third day for influenza. In HSV infection, the peak production also coincides with peak viral levels. By contrast, in influenza infection, APC production ceased between the third and fourth day despite the presence of high levels of virus until 5 days after infection. These analyses demonstrate that two quite different self-limiting infections generate the APC necessary to drive T cell responses early in infection at different rates. Understanding how such contrasting kinetics of Ag presentation impacts on the growth and size of developing protective T cell populations has important implications for the design of vaccines and immunotherapies.
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 the James S. McDonnell Foundation 21st Century Research Award/Studying Complex Systems, the National Health and Medical Research Council (Australia, to M.P.D. and G.T.B.), Howard Hughes Medical Institute (to G.T.B.), Wellcome Trust (United Kingdom, to G.T.B.), and the U.S. Department of Energy through the Los Alamos National Laboratory/Laboratory Directed Research and Development Program (to R.M.R.). M.P.D. is supported by a Sylvia and Charles Viertel Charitable Foundation senior medical research fellowship, and G.T.B. is supported by a Wellcome Trust senior overseas fellowship.
2 Current address: Commonwealth Scientific and Industrial Research Organization, Materials Science and Engineering, Clayton, VIC 3168, Australia.
3 Current address: Institute for Theoretical Biology, Humboldt-University Berlin, Berlin 10115, Germany.
4 Current address: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322.
5 Address correspondence and reprint requests to Dr. Miles P. Davenport, Complex Systems in Biology Group, Centre for Vascular Research, University of New South Wales, Kensington, NSW 2052, Australia; E-mail address: m.davenport{at}unsw.edu.au or Dr. Gabrielle T. Belz, Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia; E-mail address: belz{at}wehi.edu.au
6 Abbreviations used in this paper: DC, dendritic cell; flu, influenza A; gB, glycoprotein B; LDC, lung-derived DC; LN, lymph node; NP, nucleoprotein; p-MHC, peptide-MHC; PA, acid polymerase.
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