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Polyfunctional CD4+ T cell responses to a set of pathogenic arenaviruses provide broad population coverage

Maya F Kotturi1*, Jason Botten2, Matt Maybeno1, John Sidney1, Jean Glenn1, Huynh-Hoa Bui1, Carla Oseroff1, Shane Crotty1, Bjoern Peters1, Howard Grey1, Daniel M Altmann3, Michael J Buchmeier45 and Alessandro Sette1

Author Affiliations

1 Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, California, 92037 USA

2 Department of Medicine, The University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, Vermont, 05405-0068 USA

3 Department of Infectious Diseases and Immunity, Faculty of Medicine, Imperial College, London W12 0NN, UK

4 Department of Molecular Biology and Biochemistry, University of California, 3205 McGaugh Hall, Irvine, California, 92697-3900 USA

5 Department of Community and Environmental Medicine, University of California, 3205 McGaugh Hall, Irvine, California, 92697-3900 USA

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Immunome Research 2010, 6:4  doi:10.1186/1745-7580-6-4

Published: 17 May 2010

Abstract

Background

Several arenaviruses cause severe hemorrhagic fever and aseptic meningitis in humans for which no licensed vaccines are available. A major obstacle for vaccine development is pathogen heterogeneity within the Arenaviridae family. Evidence in animal models and humans indicate that T cell and antibody-mediated immunity play important roles in controlling arenavirus infection and replication. Because CD4+ T cells are needed for optimal CD8+ T cell responses and to provide cognate help for B cells, knowledge of epitopes recognized by CD4+ T cells is critical to the development of an effective vaccine strategy against arenaviruses. Thus, the goal of the present study was to define and characterize CD4+ T cell responses from a broad repertoire of pathogenic arenaviruses (including lymphocytic choriomeningitis, Lassa, Guanarito, Junin, Machupo, Sabia, and Whitewater Arroyo viruses) and to provide determinants with the potential to be incorporated into a multivalent vaccine strategy.

Results

By inoculating HLA-DRB1*0101 transgenic mice with a panel of recombinant vaccinia viruses, each expressing a single arenavirus antigen, we identified 37 human HLA-DRB1*0101-restricted CD4+ T cell epitopes from the 7 antigenically distinct arenaviruses. We showed that the arenavirus-specific CD4+ T cell epitopes are capable of eliciting T cells with a propensity to provide help and protection through CD40L and polyfunctional cytokine expression. Importantly, we demonstrated that the set of identified CD4+ T cell epitopes provides broad, non-ethnically biased population coverage of all 7 arenavirus species targeted by our studies.

Conclusions

The identification of CD4+ T cell epitopes, with promiscuous binding properties, derived from 7 different arenavirus species will aid in the development of a T cell-based vaccine strategy with the potential to target a broad range of ethnicities within the general population and to protect against both Old and New World arenavirus infection.