Department of Microbiology, New York University School of Medicine, New York, NY 10016;
Laboratory of Immunogenetics, Malaria Infection Biology and Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
Proc Natl Acad Sci U S A. 2017 Dec 5;114(49):E10568-E10577. doi: 10.1073/pnas.1708383114. Epub 2017 Nov 21.
Dendritic cells (DCs) are activated by pathogens to initiate and shape immune responses. We found that the activation of DCs by , the main causative agent of human malaria, induces a highly unusual phenotype by which DCs up-regulate costimulatory molecules and secretion of chemokines, but not of cytokines typical of inflammatory responses (IL-1β, IL-6, IL-10, TNF). Similar results were obtained with DCs obtained from malaria-naïve US donors and malaria-experienced donors from Mali. Contact-dependent cross-talk between the main DC subsets, plasmacytoid and myeloid DCs (mDCs) was necessary for increased chemokine and IFN-α secretion in response to the parasite. Despite the absence of inflammatory cytokine secretion, mDCs incubated with -infected erythrocytes activated antigen-specific naïve CD4 T cells to proliferate and secrete Th1-like cytokines. This unexpected response of human mDCs to exhibited a transcriptional program distinct from a classical LPS response, pointing to unique -induced activation pathways that may explain the uncharacteristic immune response to malaria.
树突状细胞 (DCs) 被病原体激活，从而引发和塑造免疫反应。我们发现，疟原虫，即人类疟疾的主要病原体，激活树突状细胞，引发一种非常特殊的表型，即树突状细胞上调共刺激分子和趋化因子的分泌，但不分泌细胞因子（IL-1β、IL-6、IL-10、TNF），这是炎症反应的典型特征。来自无疟疾经验的美国供体和来自马里的有疟疾经验的供体的 DCs 也得到了类似的结果。主要的 DC 亚群，浆细胞样和髓样 DCs (mDCs) 之间的接触依赖性交叉对话，对于寄生虫引起的趋化因子和 IFN-α 的分泌增加是必需的。尽管没有炎症细胞因子的分泌，但与感染疟原虫的红细胞孵育的 mDCs 激活抗原特异性幼稚 CD4 T 细胞增殖并分泌 Th1 样细胞因子。人类 mDCs 对 的这种出乎意料的反应表现出与经典 LPS 反应不同的转录程序，这表明存在独特的疟原虫诱导的激活途径，这可能解释了对疟疾的非典型免疫反应。
