Abstract
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.
Highlights
Yersinia pestis is the causative agent of plague, probably the most devastating disease in human history [1]
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
Passive immunization with monoclonal IgG antibodies specific for Caf1 is protective [27, 28], suggesting that opsonization is a major mechanism to overcome the resistance of Y. pestis to phagocytosis conferred by the Caf1 capsule
Summary
Yersinia pestis is the causative agent of plague, probably the most devastating disease in human history [1]. Immunization against Caf alone [12,13,14,15,16,17] or in combination with the Ysc-Yop LcrV plasmid-encoded V antigen protects mice against bubonic (18 –21) and pneumonic [22,23,24] forms of plague and has been used in human trials [25]. Passive immunization with monoclonal IgG antibodies specific for Caf is protective [27, 28], suggesting that opsonization is a major mechanism to overcome the resistance of Y. pestis to phagocytosis conferred by the Caf capsule. It has been suggested that vaccine delivery to induce protective immune responses is critically influenced by antigen structure as well as the role of adjuvants in targeting protein antigens for optimal antigen processing and presentation to T cells [32, 33].
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have