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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

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 cel...

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Autores principales: 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., Altmann, Daniel M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006929/
https://www.ncbi.nlm.nih.gov/pubmed/24788397
http://dx.doi.org/10.1371/journal.ppat.1004085
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author 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.
Altmann, Daniel M.
author_facet 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.
Altmann, Daniel M.
author_sort Ascough, Stephanie
collection PubMed
description 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.
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spelling pubmed-40069292014-05-09 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. Altmann, Daniel M. PLoS Pathog Research Article 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. Public Library of Science 2014-05-01 /pmc/articles/PMC4006929/ /pubmed/24788397 http://dx.doi.org/10.1371/journal.ppat.1004085 Text en © 2014 Ascough et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
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.
Altmann, Daniel M.
Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4(+) T Cell Immunity
title Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4(+) T Cell Immunity
title_full Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4(+) T Cell Immunity
title_fullStr Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4(+) T Cell Immunity
title_full_unstemmed Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4(+) T Cell Immunity
title_short Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4(+) T Cell Immunity
title_sort anthrax lethal factor as an immune target in humans and transgenic mice and the impact of hla polymorphism on cd4(+) t cell immunity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006929/
https://www.ncbi.nlm.nih.gov/pubmed/24788397
http://dx.doi.org/10.1371/journal.ppat.1004085
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