Human Langerhans cells express a specific TLR profile and differentially respond to viruses and Gram-positive bacteria
Human Langerhans cells express a specific TLR profile and differentially respond to viruses and Gram-positive bacteria
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DOI：
10.4049/jimmunol.177.11.7959
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发表时间：
2006-12-01
影响因子：
4.4
通讯作者：
Valladeau, Jenny
中科院分区：
文献类型：
--
作者：
Flacher, Vincent;Bouschbacher, Marielle;Valladeau, Jenny
树突状细胞(DC)是发育初级免疫应答所必需的抗原前体细胞。在多层化的上皮细胞中，朗格汉斯细胞(LC)是DC的一个重要亚群，在炎症刺激下摄取AGS并向淋巴结迁移。TLR可以通过不同的DC亚群检测病原体相关分子模式(PAMP)。人LC表达的TLR的谱系尚未确定，其对PAMP的直接反应能力也没有得到系统的研究。在这项研究中，我们首次从新鲜纯化的人皮肤LC中表达了编码TLR1、TLR2、TLR3、TLR5、TLR6和TLR10的mRNA。此外，角质形成细胞在体外表现为TLR1-5、TLR7和TLR10。因此，高度浓缩的未成熟LC有效地响应来自革兰氏阳性细菌的TLR2激动剂肽聚糖和脂磷壁酸，以及与TLR3结合的dsRNA。相比之下，LC不直接感知TLR7/8配体和来自革兰氏阴性细菌的内毒素，后者通过TLR4发出信号。TLR参与也会导致细胞因子的产生，根据检测到的PAMP而有显著差异。TLR2和TLR3配体增加IL-6和IL-8的产生，而dsRNA单独刺激肿瘤坏死因子-α的释放。引人注目的是，只有肽聚糖才能触发IL-10的分泌，从而表明对共生革兰氏阳性细菌的耐受性具有特定的功能。然而，LC不产生IL-12p70或I型IFN。总之，人类LC配备了TLR，能够直接从病毒和革兰氏阳性细菌中检测PAMP，随后的表型成熟，以及不同的细胞因子产生。这意味着LC在控制皮肤免疫反应方面具有重要作用。
Dendritic cells (DC) are APCs essential for the development of primary immune responses. In pluristratified epithelia, Langerhans cells (LC) are a critical subset of DC which take up Ags and migrate toward lymph nodes upon inflammatory stimuli. TLR allow detection of pathogen-associated molecular patterns (PAMP) by different DC subsets. The repertoire of TLR expressed by human LC is uncharacterized and their ability to directly respond to PAMP has not been systematically investigated. In this study, we show for the first time that freshly purified LC from human skin express mRNA encoding TLR1, TLR2, TLR3, TLR5, TLR6 and TLR10. In addition, keratinocytes ex vivo display TLR1-5, TLR7, and TLR10. Accordingly, highly enriched immature LC efficiently respond to TLR2 agonists peptidoglycan and lipoteichoic acid from Gram-positive bacteria, and to dsRNA which engages TLR3. In contrast, LC do not directly sense TLR7/8 ligands and LPS from Gram-negative bacteria, which signals through TLR4. TLR engagement also results in cytokine production, with marked differences depending on the PAMP detected. TLR2 and TLR3 ligands increase IL-6 and IL-8 production, while dsRNA alone stimulates TNF-alpha release. Strikingly, only peptidoglycan triggers IL-10 secretion, thereby suggesting a specific function in tolerance to commensal Gram-positive bacteria. However, LC do not produce IL-12p70 or type I IFNs. In conclusion, human LC are equipped with TLR that enable direct detection of PAMP from viruses and Gram-positive bacteria, subsequent phenotypic maturation, and differential cytokine production. This implies a significant role for LC in the control of skin immune responses.