title: Discriminating Protective from Nonprotective Plasmodium-Specific CD8+ T Cell Responses.
abstract: Despite decades of research, malaria remains a global health crisis. Current subunit vaccine approaches do not provide efficient long-term, sterilizing immunity against Plasmodium infections in humans. Conversely, whole parasite vaccinations with their larger array of target Ags have conferred long-lasting sterilizing protection to humans. Similar studies in rodent models of malaria reveal that CD8(+) T cells play a critical role in liver-stage immunity after whole parasite vaccination. However, it is unknown whether all CD8(+) T cell specificities elicited by whole parasite vaccination contribute to protection, an issue of great relevance for enhanced subunit vaccination. In this article, we show that robust CD8(+) T cell responses of similar phenotype are mounted after prime-boost immunization against Plasmodium berghei glideosome-associated protein 5041-48-, sporozoite-specific protein 20318-325-, thrombospondin-related adhesion protein (TRAP) 130-138-, or circumsporozoite protein (CSP) 252-260-derived epitopes in mice, but only CSP252-260- and TRAP130-138-specific CD8(+) T cells provide sterilizing immunity and reduce liver parasite burden after sporozoite challenge. Further, CD8(+) T cells specific to sporozoite surface-expressed CSP and TRAP proteins, but not intracellular glideosome-associated protein 50 and sporozoite-specific protein 20, efficiently recognize sporozoite-infected hepatocytes in vitro. These results suggest that: 1) protection-relevant antigenic targets, regardless of their immunogenic potential, must be efficiently presented by infected hepatocytes for CD8(+) T cells to eliminate liver-stage Plasmodium infection; and 2) proteins expressed on the surface of sporozoites may be good target Ags for protective CD8(+) T cells.
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242;
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Doll
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242;
authors.forename: Lecia L
authors.initials: LL
authors.lastname: Pewe
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242;
authors.forename: Samarchith P
authors.initials: SP
authors.lastname: Kurup
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242; Department of Pathology, University of Iowa, Iowa City, IA 52242; and Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242 john-harty@uiowa.edu.
authors.forename: John T
authors.identifier: 0000-0001-7266-2802
authors.initials: JT
authors.lastname: Harty
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D022781:Hepatocytes / Q000276:immunology / Q000469:parasitology; D007115:Immunization Schedule; D007156:Immunologic Memory; D008099:Liver / Q000469:parasitology; D008288:Malaria / Q000276:immunology* / Q000517:prevention & control; D017780:Malaria Vaccines / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology; D034101:Sporozoites / Q000276:immunology; D022223:Vaccines, Subunit / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D018984:Epitopes, T-Lymphocyte; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D022223:Vaccines, Subunit; C041595:circumsporozoite protein, Protozoan; C069428:thrombospondin-related adhesive protein, protozoan