cROSs-presentation in pDCs: An energetic (m)CAT and mouse game.
cROSs-presentation in pDCs: An energetic (m)CAT and mouse game.
复制标题
pDC 中的交叉呈现：充满活力的 (m)CAT 和小鼠游戏。
DOI：
10.1126/sciimmunol.aau2829
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发表时间：
2018
影响因子：
24.8
通讯作者：
Pillai,Asha
中科院分区：
文献类型：
--
作者：
Joshi,Sunil;Pillai,Asha
针对病毒和肿瘤的最佳免疫应答需要通过主要组织相容性复合物I类（MHC-I）分子的有效CD 8 T细胞引发，包括树突状细胞（DC）对外源性抗原的交叉呈递。尽管常规DC（cDC）在稳态下交叉呈递抗原，但浆细胞样DC（pDC）似乎需要Toll样受体（TLR）刺激以有效地将外源性抗原交叉呈递给CD 8 T细胞。TLR介导的pDC中抗原交叉呈递的上调有多种机制，但具体的细胞内途径尚不清楚。研究发现，cDC和pDC中存在一条由活性氧（ROS）调节的I类细胞交叉递呈的NOX 1/2依赖性通路。Oberkampf及其同事报道了一种新的NOX 1/2非依赖性途径，该途径允许pDC将外源性抗原交叉呈递给CD 8 T细胞。NOX依赖性ROS抑制剂能够抑制cDC和pDC中的交叉呈递，然而，在不存在NOX 1/2的TLR刺激后，仅pDC能够交叉呈递外源性抗原。通过在NOX 1/2敲除小鼠中的基因组方法，作者鉴定了TLR诱导的pDC活化过程中潜在的NOX 1/2非依赖性靶基因。基因分析表明，过氧化物降解酶，包括过氧化氢酶，一种已知的线粒体ROS产生抑制剂的显着下调。使用在其线粒体中转基因表达人过氧化氢酶的mCAT小鼠，作者表明，与cDC不同，pDC在活化后增加线粒体呼吸，在过量过氧化氢酶存在下表现出卵清蛋白抗原的交叉呈递减少和CD 8 T细胞活化减少。这些结果表明，线粒体中ROS代谢酶过氧化氢酶的抑制可以被利用来增加TLR刺激后pDC中的ROS浓度和交叉呈递。
Optimal immune responses against viruses and tumors require effective CD8 T cell priming through major histocompatibility complex class I (MHC-I) molecules, including cross-presentation of exogenous antigens by dendritic cells (DCs). Although conventional DCs (cDCs) cross-present antigen in steady state, plasmacytoid DCs (pDCs) appear to require Toll-like receptor (TLR) stimulation to effectively cross-present exogenous antigens to CD8 T cells. Multiple mechanisms have been posited for TLR–mediated up-regulation of antigen cross-presentation in pDCs, but the speci c intracellular pathways have been elusive. Understanding these mechanisms could pave the way for the development of effective therapeutics.A NOX1/2 dependent pathway for Class I–mediated cross-presentation regulated by reactive oxygen species (ROS) production has been de ned in cDCs and pDCs. Oberkampf and colleagues report a novel NOX1/2-independent pathway that allows pDCs to cross-present exogenous antigens to CD8 T cells. NOX-dependent ROS inhibitors were able to inhibit cross-presentation in both cDCs and pDCs, However, after TLR stimulation in the absence of NOX1/2, only pDCs were able to cross-present exogenous antigens. Via genomic approaches in NOX1/2 knockout mice, the authors identi ed potential NOX1/2-independent target genes during TLR-induced pDC activation. Gene pro ling suggested signi cant down-regulation of peroxide-degrading enzymes including catalase, a known inhibitor of mitochondrial ROS production. Using mCAT mice that transgenically express human catalase in their mitochondria, the authors showed that pDCs, which unlike cDCs increase mitochondrial respiration after activation, exhibited diminished cross-presentation of ovalbumin antigen and diminished CD8 T cell activation in presence of excess catalase. These ndings suggest that inhibition of the ROS-metabolizing enzyme catalase in mitochondria may be leveraged to increase ROS concentrations and cross-presentation in pDCs after TLR stimulation.