Discriminating Protective from Nonprotective Plasmodium-Specific CD8+ T Cell Responses

• Published in: The Journal of immunology (1950) 2016-05, Vol.196 (10), p.4253-4262
• Main Authors: Doll, Katherine L, Pewe, Lecia L, Kurup, Samarchith P, Harty, John T
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Protozoan - immunology; CD8-Positive T-Lymphocytes - immunology; Cells, Cultured; Disease Models, Animal; Epitopes, T-Lymphocyte - immunology; Female; Hepatocytes - immunology; Hepatocytes - parasitology; Immunization Schedule; Immunologic Memory; Liver - parasitology; Malaria - immunology; Malaria - prevention & control; Malaria Vaccines - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Plasmodium berghei - immunology; Protozoan Proteins - immunology; Sporozoites - immunology; Vaccines, Subunit - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1600155

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.