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 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.
Department of Medicine, Imperial College London, London, United Kingdom.
Stephanie
S
Ascough
Centre for Infection and Immunity, Queen's University Belfast, Belfast, United Kingdom.
Rebecca J
RJ
Ingram
Department of Medicine, Imperial College London, London, United Kingdom.
Karen K
KK
Chu
Department of Medicine, Imperial College London, London, United Kingdom.
Catherine J
CJ
Reynolds
Institute for Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Julie A
JA
Musson
Department of Infectious Disease, Erciyes University Hospital, Kayseri, Turkey.
Mehmet
M
Doganay
Department of Infectious Disease, Erciyes University Hospital, Kayseri, Turkey.
Gökhan
G
Metan
Department of Medical Genetics, Erciyes University Hospital, Kayseri, Turkey.
Yusuf
Y
Ozkul
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom.
Les
L
Baillie
Department of Medicine, Imperial College London, London, United Kingdom.
Shiranee
S
Sriskandan
BIOMET, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Stephen J
SJ
Moore
BIOMET, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Theresa B
TB
Gallagher
Defence Science Technology Laboratory, Porton Down, Salisbury, United Kingdom.
Hugh
H
Dyson
Defence Science Technology Laboratory, Porton Down, Salisbury, United Kingdom.
E Diane
ED
Williamson
Institute for Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
John H
JH
Robinson
CEA, iBiTecS, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), Gif Sur Yvette, France.
Bernard
B
Maillere
Department of Medicine, Imperial College London, London, United Kingdom.
Rosemary J
RJ
Boyton
Department of Medicine, Imperial College London, London, United Kingdom.
Daniel M
DM
Altmann
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000881:Anthrax / Q000276:immunology / Q000517:prevention & control*; D022122:Anthrax Vaccines / Q000737:chemistry / Q000627:therapeutic use; D000942:Antigens, Bacterial / Q000737:chemistry / Q000276:immunology*; D001427:Bacterial Toxins / Q000737:chemistry / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018604:Epitope Mapping; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics*; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D011110:Polymorphism, Genetic; D017192:Skin Diseases, Bacterial / Q000276:immunology / Q000517:prevention & control*; D055815:Young Adult
D022122:Anthrax Vaccines; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D006680:HLA Antigens; D016056:Immunodominant Epitopes; C030325:anthrax toxin