Mechanisms of major histocompatibility complex class II-restricted processing and presentation of the V antigen of Yersinia pestis.
We mapped mouse CD4 T-cell epitopes located in three structurally distinct regions of the V antigen of Yersinia pestis. T-cell hybridomas specific for epitopes from each region were generated to study the mechanisms of processing and presentation of V antigen by bone-marrow-derived macrophages. All three epitopes required uptake and/or processing from V antigen as well as presentation to T cells by newly synthesized major histocompatibility complex (MHC) class II molecules over a time period of 3-4 hr. Sensitivity to inhibitors showed a dependence on low pH and cysteine, serine and metalloproteinase, but not aspartic proteinase, activity. The data indicate that immunodominant epitopes from all three structural regions of V antigen were presented preferentially by the classical MHC class II-restricted presentation pathway. The requirement for processing by the co-ordinated activity of several enzyme families is consistent with the buried location of the epitopes in each region of V antigen. Understanding the structure-function relationship of multiple immunodominant epitopes of candidate subunit vaccines is necessary to inform choice of adjuvants for vaccine delivery. In the case of V antigen, adjuvants designed to target it to lysosomes are likely to induce optimal responses to multiple protective T-cell epitopes.
Shim
Ho-Ki
HK
Musculoskeletal Research Group, Clinical Medical Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.
Musson
Julie A
JA
Harper
Helen M
HM
McNeill
Hesta V
HV
Walker
Nicola
N
Flick-Smith
Helen
H
von Delwig
Alexei
A
Williamson
E Diane
ED
Robinson
John H
JH
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000942:Antigens, Bacterial / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018604:Epitope Mapping / Q000379:methods; D018984:Epitopes, T-Lymphocyte / Q000032:analysis; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000032:analysis; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D010931:Plague Vaccine / Q000276:immunology; D052899:Pore Forming Cytotoxic Proteins / Q000276:immunology*; D013329:Structure-Activity Relationship; D015010:Yersinia pestis / Q000276:immunology*
D000942:Antigens, Bacterial; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; C043908:LcrV protein, Yersinia; D010931:Plague Vaccine; D052899:Pore Forming Cytotoxic Proteins