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      Critical Role of Perforin-dependent CD8+ T Cell Immunity for Rapid Protective Vaccination in a Murine Model for Human Smallpox

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          Abstract

          Vaccination is highly effective in preventing various infectious diseases, whereas the constant threat of new emerging pathogens necessitates the development of innovative vaccination principles that also confer rapid protection in a case of emergency. Although increasing evidence points to T cell immunity playing a critical role in vaccination against viral diseases, vaccine efficacy is mostly associated with the induction of antibody responses. Here we analyze the immunological mechanism(s) of rapidly protective vaccinia virus immunization using mousepox as surrogate model for human smallpox. We found that fast protection against lethal systemic poxvirus disease solely depended on CD4 and CD8 T cell responses induced by vaccination with highly attenuated modified vaccinia virus Ankara (MVA) or conventional vaccinia virus. Of note, CD4 T cells were critically required to allow for MVA induced CD8 T cell expansion and perforin-mediated cytotoxicity was a key mechanism of MVA induced protection. In contrast, selected components of the innate immune system and B cell-mediated responses were fully dispensable for prevention of fatal disease by immunization given two days before challenge. In conclusion, our data clearly demonstrate that perforin-dependent CD8 T cell immunity plays a key role in MVA conferred short term protection against lethal mousepox. Rapid induction of T cell immunity might serve as a new paradigm for treatments that need to fit into a scenario of protective emergency vaccination.

          Author Summary

          Prophylactic use of vaccinia virus allowed eradication of human smallpox, one of the greatest successes in medicine. However there are concerns that variola virus, the infectious agent of smallpox, may be used as bioterroristic weapon and zoonotic monkeypox or cowpox remain threatening infections in humans. Thus, new developments of safe and rapidly protecting orthopoxvirus-specific vaccines have been initiated. The candidate vaccine modified vaccinia virus Ankara (MVA) was recently shown to protect against lethal systemic poxvirus disease even when applied shortly before or after infection of mice with ectromelia virus, the probably best animal model for human smallpox. Surprisingly, little is known about the protective mechanism of early immune responses elicited against orthopoxvirus infections. Here, we used the mousepox model to analyze the immunological basis of rapidly protective MVA vaccination. In contrast to common understanding of orthopoxvirus vaccine efficacy relying mainly on antibody mediated immunity, we observed unimpaired protection also in absence of B cells. Surprisingly, rapid protection by vaccination with MVA or conventional vaccinia virus was solely dependent on T cells, irrespective of the route of injection. Thus, our study suggests a key role for T cell immunity in rapidly protective immunization against orthopoxviruses and potentially other infectious agents.

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          Most cited references87

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          A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene.

          Of the various classes of antibodies that B lymphocytes can produce, class M (IgM) is the first to be expressed on the membrane of the developing cells. Pre-B cells, the precursors of B-lymphocytes, produce the heavy chain of IgM (mu chain), but not light chains. Recent data suggest that pre-B cells express mu chains on the membrane together with the 'surrogate' light chains lambda 5 and V pre B (refs 2-7). This complex could control pre-B-cell differentiation, in particular the rearrangement of the light-chain genes. We have now assessed the importance of the membrane form of the mu chain in B-cell development by generating mice lacking this chain. We disrupted one of the membrane exons of the gene encoding the mu-chain constant region by gene targeting in mouse embryonic stem cells. From these cells we derived mice heterozygous or homozygous for the mutation. B-cell development in the heterozygous mice seemed to be normal, but in homozygous animals B cells were absent, their development already being arrested at the stage of pre-B-cell maturation.
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            Duration of antiviral immunity after smallpox vaccination.

            Although naturally occurring smallpox was eliminated through the efforts of the World Health Organization Global Eradication Program, it remains possible that smallpox could be intentionally released. Here we examine the magnitude and duration of antiviral immunity induced by one or more smallpox vaccinations. We found that more than 90% of volunteers vaccinated 25-75 years ago still maintain substantial humoral or cellular immunity (or both) against vaccinia, the virus used to vaccinate against smallpox. Antiviral antibody responses remained stable between 1-75 years after vaccination, whereas antiviral T-cell responses declined slowly, with a half-life of 8-15 years. If these levels of immunity are considered to be at least partially protective, then the morbidity and mortality associated with an intentional smallpox outbreak would be substantially reduced because of pre-existing immunity in a large number of previously vaccinated individuals.
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              Defective CD8 T cell memory following acute infection without CD4 T cell help.

              The CD8+ cytotoxic T cell response to pathogens is thought to be CD4+ helper T cell independent because infectious agents provide their own inflammatory signals. Mice that lack CD4+ T cells mount a primary CD8 response to Listeria monocytogenes equal to that of wild-type mice and rapidly clear the infection. However, protective memory to a challenge is gradually lost in the former animals. Memory CD8+ T cells from normal mice can respond rapidly, but memory CD8+ T cells that are generated without CD4 help are defective in their ability to respond to secondary encounters with antigen. The results highlight a previously undescribed role for CD4 help in promoting protective CD8 memory development.
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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
                March 2012
                March 2012
                1 March 2012
                : 8
                : 3
                : e1002557
                Affiliations
                [1 ]Institute for Infectious Diseases and Zoonoses, University of Munich LMU, Muenchen, Germany
                [2 ]Paul-Ehrlich-Institut, Langen, Germany
                [3 ]Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research, Braunschweig, and Hannover Medical School, Hannover, Germany
                [4 ]Institute of Veterinary Pathology, University of Munich LMU, Muenchen, Germany
                University of Alberta, Canada
                Author notes

                Conceived and designed the experiments: MK YS AV MHL TF UK GS. Performed the experiments: MK YS AV TF MM MHL. Analyzed the data: MK YS AV TF MM KMH MHL UK GS. Contributed reagents/materials/analysis tools: KMH MM MHL UK GS. Wrote the paper: MK YS AV MHL UK GS.

                Article
                PPATHOGENS-D-11-01295
                10.1371/journal.ppat.1002557
                3291617
                22396645
                995d755d-26d3-436a-8efa-a542f3a27857
                Kremer 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
                : 15 June 2011
                : 15 January 2012
                Page count
                Pages: 16
                Categories
                Research Article
                Biology
                Immunology
                Immunity
                Microbiology
                Immunity
                Virology
                Medicine
                Clinical Immunology
                Immunity
                Vaccination
                Infectious Diseases
                Viral Diseases

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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