title: CD8+ T cells specific for a malaria cytoplasmic antigen form clusters around infected hepatocytes and are protective at the liver stage of infection.
abstract: Following Anopheles mosquito-mediated introduction into a human host, Plasmodium parasites infect hepatocytes and undergo intensive replication. Accumulating evidence indicates that CD8(+) T cells induced by immunization with attenuated Plasmodium sporozoites can confer sterile immunity at the liver stage of infection; however, the mechanisms underlying this protection are not clearly understood. To address this, we generated recombinant Plasmodium berghei ANKA expressing a fusion protein of an ovalbumin epitope and green fluorescent protein in the cytoplasm of the parasite. We have shown that the ovalbumin epitope is presented by infected liver cells in a manner dependent on a transporter associated with antigen processing and becomes a target of specific CD8(+) T cells from the T cell receptor transgenic mouse line OT-I, leading to protection at the liver stage of Plasmodium infection. We visualized the interaction between OT-I cells and infected hepatocytes by intravital imaging using two-photon microscopy. OT-I cells formed clusters around infected hepatocytes, leading to the elimination of the intrahepatic parasites and subsequent formation of large clusters of OT-I cells in the liver. Gamma interferon expressed in CD8(+) T cells was dispensable for this protective response. Additionally, we found that polyclonal ovalbumin-specific memory CD8(+) T cells induced by de novo immunization were able to confer sterile protection, although the threshold frequency of the protection was relatively high. These studies revealed a novel mechanism of specific CD8(+) T cell-mediated protective immunity and demonstrated that proteins expressed in the cytoplasm of Plasmodium parasites can become targets of specific CD8(+) T cells during liver-stage infection.
authors.affiliation: Division of Immunology, Department of Molecular Microbiology and Immunology, Nagasaki University, Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Kimura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kimura
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Matsushima
authors.forename: Mana
authors.initials: M
authors.lastname: Miyakoda
authors.forename: Kiri
authors.initials: K
authors.lastname: Honma
authors.forename: Masao
authors.initials: M
authors.lastname: Yuda
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Yui
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000469:parasitology*; D006801:Humans; D008099:Liver; D008288:Malaria; D051379:Mice; D008822:Mice, Transgenic; D009698:Nucleoproteins; D010962:Plasmodium berghei / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000953:Antigens, Protozoan; D009698:Nucleoproteins; D015800:Protozoan Proteins; C090319:peptide 31D
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