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Malaria-Specific and Nonspecific Activation of CD8⁺ T Cells during Blood Stage of Plasmodium berghei Infection¹

Mana Miyakoda^*, Daisuke Kimura^*, Masao Yuda, Yasuo Chinzei, Yoshisada Shibata, Kiri Honma^* and Katsuyuki Yui^2,*

^* Division of Immunology, Department of Molecular Microbiology and Immunology, and Atomic Bomb Disease Institute, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan; and Department of Medical Zoology, School of Medicine, Mie University, Tsu, Japan

Cerebral malaria is one of the severe complications of Plasmodium falciparum infection. Studies using a rodent model of Plasmodium berghei ANKA infection established that CD8⁺ T cells are involved in the pathogenesis of cerebral malaria. However, it is unclear whether and how Plasmodium-specific CD8⁺ T cells can be activated during the erythrocyte stage of malaria infection. We generated recombinant Plasmodium berghei ANKA expressing OVA (OVA-PbA) to investigate the parasite-specific T cell responses during malaria infection. Using this model system, we demonstrate two types of CD8⁺ T cell activations during the infection with malaria parasite. Ag (OVA)-specific CD8⁺ T cells were activated by TAP-dependent cross-presentation during infection with OVA-PbA leading to their expression of an activation phenotype and granzyme B and the development to functional CTL. These highly activated CD8⁺ T cells were preferentially sequestered in the brain, although it was unclear whether these cells were involved in the pathogenesis of cerebral malaria. Activation of OVA-specific CD8⁺ T cells in RAG2 knockout TCR-transgenic mice during infection with OVA-PbA did not have a protective role but rather was pathogenic to the host as shown by their higher parasitemia and earlier death when compared with RAG2 knockout mice. The OVA-specific CD8⁺ T cells, however, were also activated during infection with wild-type parasites in an Ag-nonspecific manner, although the levels of activation were much lower. This nonspecific activation occurred in a TAP-independent manner, appeared to require NK cells, and was not by itself pathogenic to the host.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants-in-Aid from the Ministry of Education, Science, Sports and Culture, Japan; and by the 21c COE program at Nagasaki University.

² Address correspondence and reprint requests to Dr. Katsuyuki Yui, Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4, Sakamoto, Nagasaki, 852-8523 Japan. E-mail address: katsu{at}nagasaki-u.ac.jp

³ Abbreviations used in this paper: PbA, Plasmodium berghei ANKA; OVA-PbA, recombinant Plasmodium berghei ANKA expressing OVA; WT-PbA, wild-type Plasmodium berghei ANKA; hsp, heat shock protein; DHFR-ts, dihydrofolate reductase-thymidyltransferase-ts; KO, knockout; LCMV, lymphocytic choriomeningitis virus; DC, dendritic cell; CD62L, CD62 ligand; OVAp, OVA_257–264 peptide.