Nonspecific CD8+ T Cells and Dendritic Cells/Macrophages Participate in Formation of CD8+ T Cell-Mediated Clusters against Malaria Liver-Stage Infection
Nonspecific CD8+ T Cells and Dendritic Cells/Macrophages Participate in Formation of CD8+ T Cell-Mediated Clusters against Malaria Liver-Stage Infection
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DOI：
10.1128/iai.00717-17
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发表时间：
2018-04-01
影响因子：
3.1
通讯作者：
Yui, Katsuyuki
中科院分区：
文献类型：
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作者：
Akbari, Masoud;Kimura, Kazumi;Yui, Katsuyuki
CD 8（+）T细胞是主要的效应细胞，其保护免受疟疾肝脏阶段感染，在疟原虫感染的肝细胞周围形成簇，并在与这些肝细胞长时间相互作用后消除寄生虫。我们的目的是研究特异性和非特异性CD 8（+）T细胞在簇形成和保护性免疫中的作用。为此，我们分别使用了表达卵清蛋白的伯氏疟原虫ANKA以及来自表达对卵清蛋白特异性的T细胞受体（OT-I）的转基因小鼠的CD 8（+）T细胞和对无关抗原特异性的CD 8（+）T细胞。虽然抗原特异性CD 8（+）T细胞对于簇的形成是必不可少的，但抗原特异性和非特异性CD 8（+）T细胞都加入了簇。然而，非特异性CD 8（+）T细胞对保护性免疫没有显著贡献。在受感染小鼠的肝脏中，特异性CD 8（+）T细胞表达高水平的CD 25，与局部活化效应表型相容。肝脏的体内成像显示，特异性CD 8（+）T细胞与感染肝细胞周围的CD 11 c（+）细胞相互作用。CD 11 c（+）细胞的耗竭几乎消除了肝脏中的簇，导致保护作用显著降低。这些实验揭示了肝CD 11 c（+）树突状细胞和可能的巨噬细胞在疟原虫感染肝细胞周围CD 8（+）T细胞簇形成中的重要作用。一旦寄生虫特异性CD 8（+）T细胞触发簇形成，特异性和不相关的活化CD 8（+）T细胞以趋化因子和树突状细胞依赖性方式加入簇。非特异性CD 8（+）T细胞似乎在抗疟原虫的保护性免疫中发挥有限的作用。
CD8(+) T cells are the major effector cells that protect against malaria liver-stage infection, forming clusters around Plasmodium-infected hepatocytes and eliminating parasites after a prolonged interaction with these hepatocytes. We aimed to investigate the roles of specific and nonspecific CD8(+) T cells in cluster formation and protective immunity. To this end, we used Plasmodium berghei ANKA expressing ovalbumin as well as CD8(+) T cells from transgenic mice expressing a T cell receptor specific for ovalbumin (OT-I) and CD8(+) T cells specific for an unrelated antigen, respectively. While antigen-specific CD8(+) T cells were essential for cluster formation, both antigen-specific and nonspecific CD8(+) T cells joined the clusters. However, nonspecific CD8(+) T cells did not significantly contribute to protective immunity. In the livers of infected mice, specific CD8(+) T cells expressed high levels of CD25, compatible with a local, activated effector phenotype. In vivo imaging of the liver revealed that specific CD8(+) T cells interact with CD11c(+) cells around infected hepatocytes. The depletion of CD11c(+) cells virtually eliminated the clusters in the liver, leading to a significant decrease in protection. These experiments reveal an essential role of hepatic CD11c(+) dendritic cells and presumably macrophages in the formation of CD8(+) T cell clusters around Plasmodium-infected hepatocytes. Once cluster formation is triggered by parasite-specific CD8(+) T cells, specific and unrelated activated CD8(+) T cells join the clusters in a chemokine-and dendritic cell-dependent manner. Nonspecific CD8(+) T cells seem to play a limited role in protective immunity against Plasmodium parasites.