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Anthrax lethal factor as an immune target in humans and transgenic mice and the impact of HLA polymorphism on CD4+ T Cell immunity

Ascough, Stephanie, Ingram, Rebecca J., Chu, Karen K., Reynolds, Catherine J., Musson, Julie A., Doganay, Mehmet, Metan, Gökhan, Ozkul, Yusuf, Baillie, Les, Sriskandan, Shiranee, Moore, Stephen J., Gallagher, Theresa B., Dyson, Hugh, Williamson, E. Diane, Robinson, John H., Maillere, Bernard, Boyton, Rosemary J. and Altmann, Daniel M. 2014. Anthrax lethal factor as an immune target in humans and transgenic mice and the impact of HLA polymorphism on CD4+ T Cell immunity. PLoS Pathogens 10 (5) , e1004085. 10.1371/journal.ppat.1004085

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Abstract

Bacillus anthracis produces a binary toxin composed of protective antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). Most studies have concentrated on induction of toxin-specific antibodies as the correlate of protective immunity, in contrast to which understanding of cellular immunity to these toxins and its impact on infection is limited. We characterized CD4+ T cell immunity to LF in a panel of humanized HLA-DR and DQ transgenic mice and in naturally exposed patients. As the variation in antigen presentation governed by HLA polymorphism has a major impact on protective immunity to specific epitopes, we examined relative binding affinities of LF peptides to purified HLA class II molecules, identifying those regions likely to be of broad applicability to human immune studies through their ability to bind multiple alleles. Transgenics differing only in their expression of human HLA class II alleles showed a marked hierarchy of immunity to LF. Immunogenicity in HLA transgenics was primarily restricted to epitopes from domains II and IV of LF and promiscuous, dominant epitopes, common to all HLA types, were identified in domain II. The relevance of this model was further demonstrated by the fact that a number of the immunodominant epitopes identified in mice were recognized by T cells from humans previously infected with cutaneous anthrax and from vaccinated individuals. The ability of the identified epitopes to confer protective immunity was demonstrated by lethal anthrax challenge of HLA transgenic mice immunized with a peptide subunit vaccine comprising the immunodominant epitopes that we identified.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: Anthrax; cell-mediated immunity; genetically modified animals; immune response; mouse models; peptides; T cells.
Publisher: Public Library of Science
ISSN: 1553-7374
Date of First Compliant Deposit: 30 March 2016
Last Modified: 01 Mar 2019 15:57
URI: http://orca-mwe.cf.ac.uk/id/eprint/60639

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