Research Article: Identification of Targets of CD8+ T Cell Responses to Malaria Liver Stages by Genome-wide Epitope Profiling

Date Published: May 9, 2013

Publisher: Public Library of Science

Author(s): Julius Clemence R. Hafalla, Karolis Bauza, Johannes Friesen, Gloria Gonzalez-Aseguinolaza, Adrian V. S. Hill, Kai Matuschewski, Kirk Deitsch.


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 H2b-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.

Partial Text

Malaria is responsible for an estimated 250 million episodes of clinical disease and 600,00 to 1.2 million deaths each year [1], [2]. Notwithstanding recent reductions in the burden of malaria in some endemic areas, sustained control, elimination or eradication of the disease will require a highly efficacious vaccine that prevents malaria transmission as well as reducing the burden of disease. As a benchmark in malaria vaccination, multiple immunisations of γ-radiation-attenuated Plasmodium sporozoites (γ-Spz) can protect both mice and humans against sporozoite challenge [3], [4]. The elicited protection targets the development of liver stages and completely prevents blood stage infection, resulting in sterile immunity. This experimental vaccine approach has now been replicated using other whole sporozoite immunisation strategies that include infection under drug cover and genetically arrested parasites [5]–[8]. Naturally acquired pre-erythrocytic immunity is likely multifactorial [9], involving both antibodies and T cells. However, CD8+ T cells are the prime mediators of protection after γ-Spz vaccination in mice [10], [11], and interferon (IFN)-γ is a signature of effector function [12].




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