Innate immunity limits protective adaptive immune responses against pre-erythrocytic malaria parasites
Innate immunity limits protective adaptive immune responses against pre-erythrocytic malaria parasites
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DOI：
10.1038/s41467-019-11819-0
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发表时间：
2019-09-02
影响因子：
16.6
通讯作者：
Kappe, Stefan H., I
中科院分区：
文献类型：
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作者：
Minkah, Nana K.;Wilder, Brandon K.;Kappe, Stefan H., I
用减毒的完整疟原虫子孢子进行免疫是一种有前途的疫苗接种策略。与复制缺陷型寄生虫相比，使用具有复制能力的寄生虫进行免疫可提供更好的保护，并诱导 I 型干扰素 (IFN-1) 反应，但这种 IFN-1 反应对疫苗诱导的适应性免疫是否具有有益或不利影响尚不清楚。在这里，我们表明，用具有复制能力的子孢子免疫的 IFN-1 信号传导缺陷小鼠表现出卓越的抗感染保护作用。这与优异的 CD8 T 细胞记忆相关，包括这些细胞上耗竭标记物 PD-1 和 LAG-3 的表达减少以及肝脏中记忆 CD8 T 细胞数量的增加。此外，从先前免疫过的 IFN-1 信号传导缺陷小鼠的肝脏中过继转移记忆 CD8 T 细胞，可以更好地预防肝期寄生虫。然而，IFN-1 信号传导的有害作用并不是 CD8 T 细胞固有的。总之，我们的数据表明，肝脏阶段产生的 IFN-1 信号传导通过 CD8 T 细胞外在机制损害肝脏 CD8 T 细胞记忆。
Immunization with attenuated whole Plasmodium sporozoites constitutes a promising vaccination strategy. Compared to replication-deficient parasites, immunization with replication-competent parasites confers better protection and also induces a type I IFN (IFN-1) response, but whether this IFN-1 response has beneficial or adverse effects on vaccine-induced adaptive immunity is not known. Here, we show that IFN-1 signaling-deficient mice immunized with replication-competent sporozoites exhibit superior protection against infection. This correlates with superior CD8 T cell memory including reduced expression of the exhaustion markers PD-1 and LAG-3 on these cells and increased numbers of memory CD8 T cells in the liver. Moreover, the adoptive transfer of memory CD8 T cells from the livers of previously immunized IFN-1 signaling-deficient mice confers greater protection against liver stage parasites. However, the detrimental role of IFN-1 signaling is not CD8 T cell intrinsic. Together, our data demonstrate that liver stage-engendered IFN-1 signaling impairs hepatic CD8 T cell memory via a CD8 T cell-extrinsic mechanism.