Abstract
To follow the fate of CD8+ T cells responsive to Plasmodium berghei ANKA (PbA) infection, we generated an MHC I-restricted TCR transgenic mouse line against this pathogen. T cells from this line, termed PbT-I T cells, were able to respond to blood-stage infection by PbA and two other rodent malaria species, P. yoelii XNL and P. chabaudi AS. These PbT-I T cells were also able to respond to sporozoites and to protect mice from liver-stage infection. Examination of the requirements for priming after intravenous administration of irradiated sporozoites, an effective vaccination approach, showed that the spleen rather than the liver was the main site of priming and that responses depended on CD8α+ dendritic cells. Importantly, sequential exposure to irradiated sporozoites followed two days later by blood-stage infection led to augmented PbT-I T cell expansion. These findings indicate that PbT-I T cells are a highly versatile tool for studying multiple stages and species of rodent malaria and suggest that cross-stage reactive CD8+ T cells may be utilized in liver-stage vaccine design to enable boosting by blood-stage infections.
Highlights
Malaria is a mosquito-transmitted disease found in a range of animals including man, non-human primates and rodents
Mice have been used as a convenient animal model for studying malaria, with three rodent Plasmodium species in use: (i) P. chabaudi, which can cause a disease that shows recrudescence and has many features in common with human malaria including anemia, sequestration of parasites, and metabolic acidosis [1]; (ii) P. yoelii, which has two very closely related strains that differ in their capacity to infect red blood cells and cause lethal disease [2]; and (iii) P. berghei, the ANKA strain (PbA), which has been used as a model for human cerebral malaria [3,4,5], a lethal complication of P. falciparum infection
An MHC I-restricted T cell receptor (TCR) transgenic mouse line specific for blood-stage Plasmodium berghei ANKA (PbA) was generated using TCR genes isolated from a Kb-restricted hybridoma termed B4 (Figure S1) originally derived from a T cell line isolated from a B6 mouse infected with blood-stage PbA
Summary
Malaria is a mosquito-transmitted disease found in a range of animals including man, non-human primates and rodents. The pathological process underlying experimental cerebral malaria (ECM) seen in PbA infections offers insight into immune-mediated pathology in general, providing a rigorous experimental approach that can be manipulated to decipher various cellular and molecular contributions. In this rodent model, various cell types and cytokines have been reported to contribute to lethal ECM, with CD8+ T cells a Author Summary
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