title: Identification of targets of CD8⁺ T cell responses to malaria liver stages by genome-wide epitope profiling.
abstract: CD8⁺ T cells mediate immunity against Plasmodium liver stages. However, the paucity of parasite-specific epitopes of CD8⁺ T cells has limited our current understanding of the mechanisms influencing the generation, maintenance and efficiency of these responses. To identify antigenic epitopes in a stringent murine malaria immunisation model, we performed a systematic profiling of H(2b)-restricted peptides predicted from genome-wide analysis. We describe the identification of Plasmodium berghei (Pb) sporozoite-specific gene 20 (S20)- and thrombospondin-related adhesive protein (TRAP)-derived peptides, termed PbS20₃₁₈ and PbTRAP₁₃₀ respectively, as targets of CD8⁺ T cells from C57BL/6 mice vaccinated by whole parasite strategies known to protect against sporozoite challenge. While both PbS20₃₁₈ and PbTRAP₁₃₀ elicit effector and effector memory phenotypes in both the spleens and livers of immunised mice, only PbTRAP₁₃₀-specific CD8⁺ T cells exhibit in vivo cytotoxicity. Moreover, PbTRAP₁₃₀-specific, but not PbS20₃₁₈-specific, CD8⁺ T cells significantly contribute to inhibition of parasite development. Prime/boost vaccination with PbTRAP demonstrates CD8⁺ T cell-dependent efficacy against sporozoite challenge. We conclude that PbTRAP is an immunodominant antigen during liver-stage infection. Together, our results underscore the presence of CD8⁺ T cells with divergent potencies against distinct Plasmodium liver-stage epitopes. Our identification of antigen-specific CD8⁺ T cells will allow interrogation of the development of immune responses against malaria liver stages.
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom. Julius.Hafalla@lshtm.ac.uk
authors.forename: Julius Clemence R
authors.initials: JC
authors.lastname: Hafalla
authors.forename: Karolis
authors.initials: K
authors.lastname: Bauza
authors.forename: Johannes
authors.initials: J
authors.lastname: Friesen
authors.forename: Gloria
authors.initials: G
authors.lastname: Gonzalez-Aseguinolaza
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.forename: Kai
authors.initials: K
authors.lastname: Matuschewski
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology* / Q000302:isolation & purification; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000302:isolation & purification; D055106:Genome-Wide Association Study; D008099:Liver / Q000469:parasitology; D008288:Malaria / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei; D015800:Protozoan Proteins / Q000276:immunology / Q000302:isolation & purification; D034101:Sporozoites / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D018984:Epitopes, T-Lymphocyte; D015800:Protozoan Proteins; C069428:thrombospondin-related adhesive protein, protozoan