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. 2008 Sep 23;105(38):14509-14.
doi: 10.1073/pnas.0806727105. Epub 2008 Sep 17.

Blood-stage Plasmodium infection induces CD8+ T lymphocytes to parasite-expressed antigens, largely regulated by CD8alpha+ dendritic cells

Rachel J Lundie  1 , Tania F de Koning-Ward, Gayle M Davey, Catherine Q Nie, Diana S Hansen, Lei Shong Lau, Justine D Mintern, Gabrielle T Belz, Louis Schofield, Francis R Carbone, Jose A Villadangos, Brendan S Crabb, William R Heath
Affiliations

Blood-stage Plasmodium infection induces CD8+ T lymphocytes to parasite-expressed antigens, largely regulated by CD8alpha+ dendritic cells

Rachel J Lundie et al. Proc Natl Acad Sci U S A. .

Abstract

Although CD8(+) T cells do not contribute to protection against the blood stage of Plasmodium infection, there is mounting evidence that they are principal mediators of murine experimental cerebral malaria (ECM). At present, there is no direct evidence that the CD8(+) T cells mediating ECM are parasite-specific or, for that matter, whether parasite-specific CD8(+) T cells are generated in response to blood-stage infection. To resolve this and to define the cellular requirements for such priming, we generated transgenic P. berghei parasites expressing model T cell epitopes. This approach was necessary as MHC class I-restricted antigens to blood-stage infection have not been defined. Here, we show that blood-stage infection leads to parasite-specific CD8(+) and CD4(+) T cell responses. Furthermore, we show that P. berghei-expressed antigens are cross-presented by the CD8alpha(+) subset of dendritic cells (DC), and that this induces pathogen-specific cytotoxic T lymphocytes (CTL) capable of lysing cells presenting antigens expressed by blood-stage parasites. Finally, using three different experimental approaches, we provide evidence that CTL specific for parasite-expressed antigens contribute to ECM.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Transgenic P. berghei express model T and B cell epitopes and GFP. (A) Schematic of the polytope encoding model T and B cell epitopes fused to GFP. The fusion protein was placed under the P. berghei EF-1α promoter. (B) Parasitemia curves for P. berghei ANKA (PbA), PbG, and PbTG in B6 mice. Data pooled from two experiments; n represents total number of mice per group. Error bars represent SEM. (C) Survival curves for PbA, PbG, and PbTG in B6 mice. Data pooled from three to five experiments; n represents total number of mice per group. The shaded area indicates the time when mice displayed ECM symptoms. Mice dying after this time were killed on ethical grounds due to anemia associated with hyperparasitemia.
Fig. 2.
Fig. 2.
Transgenic P. berghei antigens are functionally expressed and presented to pathogen-specific T cells during blood-stage infection. Proliferation of CD8+ transgenic T cells (A) and CD4+ transgenic T cells (B) in B6 or BALB/c mice after infection with PbTG or PbG.
Fig. 3.
Fig. 3.
Transgenic P. berghei blood-stage infection induces functional CTL. (A) Percentage specific lysis of OVA257–264 peptide-pulsed target cells by endogenous CTL generated in the spleens of B6 mice infected with PbTG for 3–6 days. All values are relative to naive mice, which were designated as 0% lysis. (B) Expansion of endogenous gB-tetramer-specific CD8+ T cells in the spleen and blood of B6 mice infected with PbTG or PbG for 7 days. Open circles represent values for individual mice; horizontal bars represent values of the mean.
Fig. 4.
Fig. 4.
CD8α DC cross-present P. berghei-expressed transgenic antigens to stimulate CD8+ T cells. Proliferation of OT-I (A), CL4 (B), and HNT (C) transgenic T cells in the presence of conventional DC subtypes isolated from the spleens of B6 or BALB/c mice on day 3 after infection with PbTG. Data pooled from two to four experiments. Error bars represent SEM.
Fig. 5.
Fig. 5.
CTL specific for parasite-expressed antigens are capable of infiltrating the brain and causing lethal disease. (A) Representative flow cytometry profiles of brain-infiltrating lymphocytes isolated from B6 mice left uninfected (naive) or infected with PbTG or PbG for 5 days. Mice were adoptively transferred with Ly5.1+ OT-I and OT-II T cells on day 1 post-infection. The percentage of cells in each quadrant is indicated. (B) Survival curves for B6 mice after adoptive transfer of OT-I CTL on day 2 post-infection with PbTG or PbG. Control mice did not receive OT-I CTL. Data pooled from three experiments; n represents total number of mice per group. The p values calculated using the Wilcoxon rank-sum test are indicated.
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