Lookup NU author(s): Dr Julie Musson,
Professor John Robinson
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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 majorimpact 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 fromhumans previously infected with cutaneous anthrax and from vaccinated individuals. The ability of the identified epitopes to confer protective immunitywas demonstrated by lethal anthrax challenge of HLA transgenic mice immunized with a peptide subunit vaccine comprising the immunodominant epitopes that we identified.
Author(s): Ascough S, Ingram RJ, Chu KK, Reynolds CJ, Musson JA, Doganay M, Metan G, Ozkul Y, Baillie L, Sriskandan S, Moore SJ, Gallagher TB, Dyson H, Williamson ED, Robinson JH, Maillere B, Boyton RJ, Altmann DM
Publication type: Article
Publication status: Published
Journal: PLOS Pathogens
Print publication date: 01/05/2014
Acceptance date: 07/03/2014
Date deposited: 04/07/2014
ISSN (print): 1553-7366
Publisher: Public Library of Science
PubMed id: e1004085
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