Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity
Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity
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CD8- DC 中的 I 型 IFN 信号会损害 Th1 依赖性疟疾免疫力
DOI：
10.1172/jci70698
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发表时间：
2014-06-01
影响因子：
15.9
通讯作者：
Engwerda, Christian R.
中科院分区：
文献类型：
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作者：
Haque, Ashraful;Best, Shannon E.;Engwerda, Christian R.
许多病原体，包括病毒、细菌和原生动物寄生虫，通过激活I型IFN信号抑制细胞免疫反应。最近的证据表明，免疫抑制和对疟原虫的易感性是由I型干扰素介导的；然而，目前尚不清楚I型IFN如何抑制对血期疟原虫的免疫。在实验性重症疟疾期间，CD4(+) Th细胞反应受到抑制，传统DC （cDC）功能因未知机制而受到限制。在这里，我们验证了I型IFN信号在小鼠疟原虫感染期间直接损害cDC功能的假设。通过使用cDC特异性ifnar1缺陷小鼠和混合BM嵌合体，我们发现I型TEN信号直接影响cDC功能，限制了cDC启动产生ifn - γ的Th1细胞的能力。尽管I型IFN信号可以调节脾cDCs的所有亚群，但CD8(-) cDCs特别敏感，在I型IFN的作用下表现出减少的吞噬和促进th1的特性。此外，响应疟原虫感染的快速和系统性IFN- α产生需要cdc自身的I型IFN信号传导，揭示了它们对前馈细胞因子信号传导回路的贡献。总之，这些数据表明，在CD8-脾脏cdc中，I型IFN信号的消除是增强Th1对疟原虫和其他I型IFN诱导病原体反应的一种途径。
Many pathogens, including viruses, bacteria, and protozoan parasites, suppress cellular immune responses through activation of type I IFN signaling. Recent evidence suggests that immune suppression and susceptibility to the malaria parasite, Plasmodium, is mediated by type I IFN; however, it is unclear how type I IFN suppresses immunity to blood-stage Plasmodium parasites. During experimental severe malaria, CD4(+) Th cell responses are suppressed, and conventional DC (cDC) function is curtailed through unknown mechanisms. Here, we tested the hypothesis that type I IFN signaling directly impairs cDC function during Plasmodium infection in mice. Using cDC-specific IFNAR1-deficient mice, and mixed BM chimeras, we found that type I TEN signaling directly affects cDC function, limiting the ability of cDCs to prime IFN-gamma-producing Th1 cells. Although type I IFN signaling modulated all subsets of splenic cDCs, CD8(-) cDCs were especially susceptible, exhibiting reduced phagocytic and Th1-promoting properties in response to type I IFNs. Additionally, rapid and systemic IFN-alpha production in response to Plasmodium infection required type I IFN signaling in cDCs themselves, revealing their contribution to a feed-forward cytokine-signaling loop. Together, these data suggest abrogation of type I IFN signaling in CD8- splenic cDCs as an approach for enhancing Th1 responses against Plasmodium and other type I IFN-inducing pathogens.