CD200 receptor controls sex-specific TLR7 responses to viral infection.
CD200 receptor controls sex-specific TLR7 responses to viral infection.
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DOI：
10.1371/journal.ppat.1002710
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Meyaard L
中科院分区：
文献类型：
--
作者：
Karnam G;Rygiel TP;Raaben M;Grinwis GC;Coenjaerts FE;Ressing ME;Rottier PJ;de Haan CA;Meyaard L
免疫检查点，如抑制性CD200受体（CD200R），在微生物感染期间平衡免疫系统方面发挥双重作用。一方面，这些抑制信号防止过度的免疫介导的病理，但另一方面，它们可能损害病原体的清除。我们在两种不同的病毒感染模型中研究了抑制性CD200-CD200R轴对清除和病理学的影响。我们发现，缺乏CD200 R信号强烈增强I型干扰素（IFN）的生产和病毒清除，并改善小鼠肝炎冠状病毒（MHV）感染的结果，特别是在雌性小鼠。已知MHV清除依赖于Toll样受体7（TLR7）介导的I型IFN产生，并且先前已经报道了人类TLR7应答的性别差异。因此，我们假设，CD200 R连接抑制TLR7的反应和释放这种抑制扩大TLR7信号的性别差异。这一假设得到了我们的研究结果的支持，即体内施用合成的TLR7配体导致I型IFN的产生增强，特别是在雌性Cd200 −/−小鼠中，并且CD200 R连接抑制体外TLR7信号传导。在甲型流感病毒感染中，我们表明病毒清除是由性别决定的，而不是由CD 200 R信号传导决定的。然而，在甲型流感病毒感染中缺乏CD200 R导致女性肺中性粒细胞流入和病理学增强。因此，CD200-CD200R和性别是共同决定病毒感染结果的宿主因素。我们的数据预测，在治疗靶向CD200-CD200R后，对病毒感染的有益和病理性免疫应答存在性别偏倚。免疫反应需要精心策划，以防止由于过度活跃的免疫系统引起的疾病。免疫检查点由免疫抑制受体提供，其设置激活阈值并抑制免疫系统。在病毒感染的情况下，这可以防止由免疫系统诱导的病理，但另一方面可能会阻止病毒的充分清除。在本文中，我们表明，在小鼠中去除这样的免疫检查点会导致冠状病毒的快速清除，但在流感病毒感染的情况下也会导致更多的免疫诱导疾病症状。我们主要在雌性小鼠中观察到这一点。我们证明，这个特定的检查点抑制了女性自然更强的抗病毒反应。这一检查点的释放扩大了这些性别差异。我们的研究结果对该途径阻断剂的治疗用途具有重要意义，目前该途径阻断剂正在临床试验中用于治疗癌症，因为我们预测女性患者对此类疗法的反应更强。
Immunological checkpoints, such as the inhibitory CD200 receptor (CD200R), play a dual role in balancing the immune system during microbial infection. On the one hand these inhibitory signals prevent excessive immune mediated pathology but on the other hand they may impair clearance of the pathogen. We studied the influence of the inhibitory CD200-CD200R axis on clearance and pathology in two different virus infection models. We find that lack of CD200R signaling strongly enhances type I interferon (IFN) production and viral clearance and improves the outcome of mouse hepatitis corona virus (MHV) infection, particularly in female mice. MHV clearance is known to be dependent on Toll like receptor 7 (TLR7)-mediated type I IFN production and sex differences in TLR7 responses previously have been reported for humans. We therefore hypothesize that CD200R ligation suppresses TLR7 responses and that release of this inhibition enlarges sex differences in TLR7 signaling. This hypothesis is supported by our findings that in vivo administration of synthetic TLR7 ligand leads to enhanced type I IFN production, particularly in female Cd200−/− mice and that CD200R ligation inhibits TLR7 signaling in vitro. In influenza A virus infection we show that viral clearance is determined by sex but not by CD200R signaling. However, absence of CD200R in influenza A virus infection results in enhanced lung neutrophil influx and pathology in females. Thus, CD200-CD200R and sex are host factors that together determine the outcome of viral infection. Our data predict a sex bias in both beneficial and pathological immune responses to virus infection upon therapeutic targeting of CD200-CD200R. Immune responses need to be carefully orchestrated to prevent disease due to an overactive immune system. Immunological checkpoints are provided by immune inhibitory receptors, which set a threshold for activation and dampen the immune system. In the case of a viral infection, this prevents pathology induced by the immune system, but on the other hand may prevent adequate removal of the virus. In this paper, we show that removal of such an immunological checkpoint in mice leads to rapid removal of corona virus, but also to more immune-induced disease symptoms in case of influenza virus infection. We observe this predominantly in female mice. We demonstrate that this particular checkpoint inhibits anti-viral responses that are naturally stronger in females. Release of this checkpoint enlarges these sex differences. Our findings have major implications for therapeutic use of blockers of this pathway, which are currently in clinical trials for the treatment of cancer, as we predict that female patients will have a stronger response to such therapeutics.
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影响因子：
7.9
作者：
Klein SL;Passaretti C;Anker M;Olukoya P;Pekosz A
通讯作者：
Pekosz A
DOI：
10.1038/nri2394
发表时间：
2008-09
期刊：
Nature reviews. Immunology
影响因子：
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作者：
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影响因子：
168.9
作者：
Farzadegan, H;Hoover, DR;Vlahov, D
通讯作者：
Vlahov, D
影响因子：
5.4
作者：
Raaben, Matthijs;Grinwis, Guy C. M.;de Haan, Cornelis A. M.
通讯作者：
de Haan, Cornelis A. M.
DOI：
10.1016/s1473-3099(10)70049-9
发表时间：
2010-05
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
Klein SL;Jedlicka A;Pekosz A
通讯作者：
Pekosz A