Abstract
Merozoite Surface Protein 1 is expressed on the surface of malaria merozoites and is important for invasion of the malaria parasite into erythrocytes. MSP1-specific CD4 T cell responses and antibody can confer protective immunity in experimental models of malaria. In this study we explore the contributions of cathepsins D and E, two aspartic proteinases previously implicated in antigen processing, to generating MSP1 CD4 T-cell epitopes for presentation. The absence of cathepsin D, a late endosome/lysosomal enzyme, is associated with a reduced presentation of MSP1 both following in vitro processing of the epitope MSP1 from infected erythrocytes by bone marrow-derived dendritic cells, and following in vivo processing by splenic CD11c+ dendritic cells. By contrast, processing and presentation of the soluble recombinant protein fragment of MSP1 is unaffected by the absence of cathepsin D, but is inhibited when both cathepsin D and E are absent. The role of different proteinases in generating the CD4 T cell repertoire, therefore, depends on the context in which an antigen is introduced to the immune system.
Highlights
Protective immunity against blood-stage malaria is dependent on CD4 T cells and B cells [1]
The peptides bind to class II Major Histocompatibility Complex (MHC) within endosomes, and the peptide/ MHC complex is displayed at the cell surface for subsequent recognition by specific T cells
In this study we demonstrate that the absence of cathepsin D significantly inhibits the T cell response to two epitopes of P. chabaudi cabaudi MSP1 antigen, either after processing of infected erythrocytes by bone marrow derived dendritic cells (DC) in vitro, or by splenic DC during in vivo infection
Summary
Protective immunity against blood-stage malaria is dependent on CD4 T cells and B cells [1]. In Plasmodium chabaudi (AS) infections in mice, development of IFNc-producing Th1 cells and antibody are required to control parasitemia. CD4 Th1 T cells are implicated in driving inflammatory responses linked to pathology. Despite the importance of CD4 T cells in malaria infections, the factors governing their activation, differentiation and regulation are not fully understood. The primary activation of CD4 T cells requires that the antigen is processed and presented by dendritic cells (DC) [2]. The peptides bind to class II Major Histocompatibility Complex (MHC) within endosomes, and the peptide/ MHC complex is displayed at the cell surface for subsequent recognition by specific T cells. The interaction between a specific T cell receptor and its cognate MHC/peptide complex is the primary recognition driving subsequent T cell activation, differentiation and proliferation
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