Mechanisms of major histocompatibility complex class II‐restricted processing and presentation of the V antigen of <i>Yersinia pestis</i>

Shim, Ho‐Ki; Musson, Julie A.; Harper, Helen; McNeill, Hesta; Walker, Nicola; Flick-Smith, Helen C.; Delwig, Alexei von; Williamson, E. Diane; Robinson, John H.

doi:10.1111/j.1365-2567.2006.02447.x

Cited by 23 publications

(22 citation statements)

References 61 publications

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“…This could explain the molecular attributes of protective LcrV antibodies, which must block type III injection of immune cells (48) and thereby enable phagocytosis and clearance of the invading pathogen by macrophages and polymorphonuclear leukocytes (15). Second, small changes in the LcrV sequence (for example, deletion of residues 270 to 300) could precipitate fundamental changes in the antibody repertoire of immunized animals, likely because the mechanisms by which LcrV is perceived by the host immune system have been altered (54).…”

Section: Discussionmentioning

confidence: 99%

Immunization with Recombinant V10 Protects Cynomolgus Macaques from Lethal Pneumonic Plague

et al. 2008

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Vaccine and therapeutic strategies that prevent infections with Yersinia pestis have been sought for over a century. Immunization with live attenuated (nonpigmented) strains and immunization with subunit vaccines containing recombinant low-calcium-response V antigen (rLcrV) and recombinant F1 (rF1) antigens are considered effective in animal models. Current antiplague subunit vaccines in development for utilization in humans contain both antigens, either as equal concentrations of the two components (rF1 plus rLcrV) or as a fusion protein (rF1-rLcrV). Here, we show that immunization with either purified rLcrV (a protein at the tip of type III needles) or a variant of this protein, recombinant V10 (rV10) (lacking amino acid residues 271 to 300), alone or in combination with rF1, prevented pneumonic lesions and disease pathogenesis. In addition, passive immunization studies showed that specific antibodies of macaques immunized with rLcrV, rV10, or rF1, either alone or in combination, conferred protection against bubonic plague challenge in mice. Finally, we found that when we compared the reactivities of anti-rLcrV and anti-rV10 immune sera from cynomolgus macaques, BALB/c mice, and brown Norway rats with LcrV-derived peptides, rV10, but not rLcrV immune sera, lacked antibodies recognizing linear LcrV oligopeptides.

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Section: Discussionmentioning

confidence: 99%

Immunization with Recombinant V10 Protects Cynomolgus Macaques from Lethal Pneumonic Plague

et al. 2008

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“…Subsequently, human leucocyte antigen (HLA)-transgenic mice have been used to identify human T cell epitopes in the F1 and V antigens and an HLA DR1-restricted T cell epitope has been described in the C-terminal sequence (amino acids 141-160) of F1 [90]. The epitope mapping of V antigen is also ongoing in the mouse [91] as well as in HLA transgenic mice. If protective function can be ascribed to some of these epitopes, they hold great potential as target sequences against which to screen for recognition by ex-vivo T cells from human vaccinees.…”

Section: T Cell Epitope Mapping Of F1 and V Antigensmentioning

confidence: 99%

Protecting against plague: towards a next-generation vaccine

Williamson

Oyston

2013

Clinical and Experimental Immunology

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SummaryThe causative organism of plague is the bacterium Yersinia pestis. Advances in understanding the complex pathogenesis of plague infection have led to the identification of the F1-and V-antigens as key components of a nextgeneration vaccine for plague, which have the potential to be effective against all forms of the disease. Here we review the roles of F1-and V-antigens in the context of the range of virulence mechanisms deployed by Y. pestis, in order to develop a greater understanding of the protective immune responses required to protect against plague.

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“…However, few candidate vaccine antigens have been sub-jected to a detailed study of the mechanisms of antigen presentation of multiple epitopes (34,35). We investigated antigen presentation of rCaf1 to helper T cells and observed major differences between epitopes depending on their location within the recently solved Caf1 structure (10).…”

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confidence: 99%

Sequential Proteolytic Processing of the Capsular Caf1 Antigen of Yersinia pestis for Major Histocompatibility Complex Class II-restricted Presentation to T Lymphocytes

Musson

Morton

Walker

et al. 2006

Journal of Biological Chemistry

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We studied the mechanisms of antigen presentation of CD4 T cell epitopes of the capsular Caf1 antigen of Yersinia pestis using murine bone marrow macrophages as antigen presenting cells and T cell hybridomas specific for major histocompatibility complex (MHC) class II-restricted epitopes distributed throughout the Caf1 sequence. The data revealed diversity in the pathways used and the degrees of antigen processing required depending on the structural context of epitopes within the Caf1 molecule. Two epitopes in the carboxyl-terminal globular domain were presented by newly synthesized MHC class II after low pH-dependent lysosomal processing, whereas an epitope located in a flexible amino-terminal strand was presented by mature MHC class II independent of low pH and with no detectable requirement for proteolytic processing. A fourth epitope located between the two regions of Caf1 showed intermediate behavior. The data are consistent with progressive unfolding and cleavage of rCaf1 from the amino terminus as it traverses the endosomal pathway, the availability of epitopes determining which pool of MHC class II is preferentially loaded. The Caf1 capsular protein is a component of second generation plague vaccines and an understanding of the mechanisms and pathways of MHC class II-restricted presentation of multiple epitopes from this candidate vaccine antigen should inform the choice of delivery systems and adjuvants that target vaccines successfully to appropriate intracellular locations to induce protective immune responses against as wide a T cell repertoire as possible.

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Mechanisms of major histocompatibility complex class II‐restricted processing and presentation of the V antigen of Yersinia pestis

Cited by 23 publications

References 61 publications

Immunization with Recombinant V10 Protects Cynomolgus Macaques from Lethal Pneumonic Plague

Immunization with Recombinant V10 Protects Cynomolgus Macaques from Lethal Pneumonic Plague

Protecting against plague: towards a next-generation vaccine

Sequential Proteolytic Processing of the Capsular Caf1 Antigen of Yersinia pestis for Major Histocompatibility Complex Class II-restricted Presentation to T Lymphocytes

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