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      Coxsackievirus B3 Inhibits Antigen Presentation In Vivo, Exerting a Profound and Selective Effect on the MHC Class I Pathway

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          Abstract

          Many viruses encode proteins whose major function is to evade or disable the host T cell response. Nevertheless, most viruses are readily detected by host T cells, and induce relatively strong T cell responses. Herein, we employ transgenic CD4 + and CD8 + T cells as sensors to evaluate in vitro and in vivo antigen presentation by coxsackievirus B3 (CVB3), and we show that this virus almost completely inhibits antigen presentation via the MHC class I pathway, thereby evading CD8 + T cell immunity. In contrast, the presentation of CVB3-encoded MHC class II epitopes is relatively unencumbered, and CVB3 induces in vivo CD4 + T cell responses that are, by several criteria, phenotypically normal. The cells display an effector phenotype and mature into multi-functional CVB3-specific memory CD4 + T cells that expand dramatically following challenge infection and rapidly differentiate into secondary effector cells capable of secreting multiple cytokines. Our findings have implications for the efficiency of antigen cross-presentation during coxsackievirus infection.

          Author Summary

          Many viruses—for example, large DNA viruses like smallpox virus and herpesviruses—encode several proteins whose major function is to combat the host's immune response, but these proteins usually battle in vain; in general, the mammalian immune system is sufficiently accomplished to penetrate this viral armor, allowing the infected animal to mount an immune response that can eradicate—or, at least, suppress—the infectious agent. Here, we show that coxsackievirus, a small RNA virus, carries a far more powerful punch than its larger DNA cousins; it almost entirely evades detection by host CD8 + T cells, which usually are one of the key components of an antiviral immune response. How does the virus achieve such success? Normally, when a virus infects a cell, certain host proteins capture small fragments of the virus and display them on the cell's surface, allowing them to be detected by the host immune system—usually, by cells called CD8 + T cells. We show here that coxsackievirus very effectively prevents these “flags” from reaching the cell surface in a form that can trigger naïve T cells to respond; in effect, the virus renders the cell “invisible” to CD8 + T cells, creating a cocoon in which the virus can multiply undisturbed by host immunity.

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          Most cited references60

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          Endogenous MHC class II processing of a viral nuclear antigen after autophagy.

          CD4+ T cells classically recognize antigens that are endocytosed and processed in lysosomes for presentation on major histocompatibility complex (MHC) class II molecules. Here, endogenous Epstein-Barr virus nuclear antigen 1 (EBNA1) was found to gain access to this pathway by autophagy. On inhibition of lysosomal acidification, EBNA1, the dominant CD4+ T cell antigen of latent Epstein-Barr virus infection, slowly accumulated in cytosolic autophagosomes. In addition, inhibition of autophagy decreased recognition by EBNA1-specific CD4+ T cell clones. Thus, lysosomal processing after autophagy may contribute to MHC class II-restricted surveillance of long-lived endogenous antigens including nuclear proteins relevant to disease.
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            Estimating the Precursor Frequency of Naive Antigen-specific CD8 T Cells

            The constraint of fitting a diverse repertoire of antigen specificities in a limited total population of lymphocytes results in the frequency of naive cells specific for any given antigen (defined as the precursor frequency) being below the limit of detection by direct measurement. We have estimated this precursor frequency by titrating a known quantity of antigen-specific cells into naive recipients. Adoptive transfer of naive antigen-specific T cell receptor transgenic cells into syngeneic nontransgenic recipients, followed by stimulation with specific antigen, results in activation and expansion of both donor and endogenous antigen-specific cells in a dose-dependent manner. The precursor frequency is equal to the number of transferred cells when the transgenic and endogenous responses are of equal magnitude. Using this method we have estimated the precursor frequency of naive CD8 T cells specific for the H-2Db–restricted GP33–41 epitope of LCMV to be 1 in 2 × 105. Thus, in an uninfected mouse containing ∼2-4 × 107 naive CD8 T cells we estimate there to be 100–200 epitope-specific cells. After LCMV infection these 100–200 GP33-specific naive CD8 T cells divide >14 times in 1 wk to reach a total of ∼107 cells. Approximately 5% of these activated GP33-specific effector CD8 T cells survive to generate a memory pool consisting of ∼5 × 105 cells. Thus, an acute LCMV infection results in a >1,000-fold increase in precursor frequency of DbGP33-specific CD8 T cells from 2 × 102 naive cells in uninfected mice to 5 × 105 memory cells in immunized mice.
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              Initial T cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8(+) T cell response to infection.

              Adoptive-transfer experiments with relatively large input numbers ( approximately 10(6)) of T cell receptor-transgenic (TCR-tg) T cells are widely used to model endogenous T cell responses to infection or immunization. We show that input numbers of naive TCR-tg T cells sufficient to squelch the endogenous response to the same epitope substantially alter the kinetics, proliferative expansion, phenotype, and efficiency of memory generation by the TCR-tg T cells in response to infection. Thus, responses from nonphysiologic input numbers of TCR-tg T cells fail to accurately mimic the endogenous T cell response. Importantly, seeding as few as approximately 10-50 TCR-tg T cells, which constitute a fraction of the endogenous repertoire, allowed vigorous proliferation and analysis of TCR-tg cells after infection in a scenario representing normal physiology for any individual TCR. These data strongly suggest that modeling the endogenous T cell response with TCR-tg cells will require every effort to approximate the endogenous precursor frequency.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                October 2009
                October 2009
                16 October 2009
                : 5
                : 10
                : e1000618
                Affiliations
                [1 ]Department of Immunology and Microbial Science, SP30-2110, The Scripps Research Institute, La Jolla, California, United States of America
                [2 ]Department of Biology, San Diego State University, San Diego, California, United States of America
                University of Pennsylvania School of Medicine, United States of America
                Author notes

                Conceived and designed the experiments: CCK JKW RF JLW. Performed the experiments: CCK SH JKW CTF RF. Analyzed the data: CCK JKW JLW. Wrote the paper: CCK JLW.

                Article
                09-PLPA-RA-0183R3
                10.1371/journal.ppat.1000618
                2757675
                19834548
                5b32bece-8a76-4ade-b6fc-981bd3794fd3
                Kemball et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 10 February 2009
                : 14 September 2009
                Page count
                Pages: 17
                Categories
                Research Article
                Immunology/Antigen Processing and Recognition
                Immunology/Immune Response
                Immunology/Immunity to Infections
                Infectious Diseases/Viral Infections
                Virology/Animal Models of Infection
                Virology/Host Antiviral Responses
                Virology/Immune Evasion

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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