Malaria-specific and nonspecific activation of CD8+ T cells during blood stage of Plasmodium berghei infection
Malaria-specific and nonspecific activation of CD8+ T cells during blood stage of Plasmodium berghei infection
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DOI：
10.4049/jimmunol.181.2.1420
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发表时间：
2008-07-15
影响因子：
4.4
通讯作者：
Yui, Katsuyuki
中科院分区：
文献类型：
--
作者：
Miyakoda, Mana;Kimura, Daisuke;Yui, Katsuyuki
脑型疟疾是恶性疟原虫感染的严重并发症之一。使用伯氏疟原虫ANKA感染的啮齿动物模型的研究证实，CD 8（+）T细胞参与脑型疟疾的发病机制。然而，目前尚不清楚疟原虫特异性CD 8（+）T细胞是否以及如何在疟疾感染的红细胞阶段被激活。我们构建了表达OVA的伯氏疟原虫ANKA重组体（OVA-PbA），以研究疟原虫感染过程中疟原虫特异性T细胞反应。利用这个模型系统，我们证明了两种类型的CD 8（+）T细胞活化过程中感染疟原虫。在OVA-PbA感染过程中，Ag（OVA）特异性CD 8（+）T细胞通过TAP依赖性交叉呈递被激活，导致其表达活化表型和颗粒酶B，并发育为功能性CTL。这些高度活化的CD 8（+）T细胞优先被隔离在大脑中，尽管尚不清楚这些细胞是否参与脑型疟疾的发病机制。在用OVA-PbA感染期间，RAG 2敲除TCR转基因小鼠中OVA特异性CD 8（+）T细胞的激活不具有保护作用，而是对宿主具有致病性，如与RAG 2敲除小鼠相比，其较高的寄生虫血症和较早的死亡所示。然而，OVA特异性CD 8（+）T细胞在感染野生型寄生虫期间也以Ag非特异性方式被激活，尽管激活水平要低得多。这种非特异性激活以TAP独立的方式发生，似乎需要NK细胞，并且本身对宿主没有致病性。
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.