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Dendritic cells control fibroblastic reticular network tension and lymph node expansion

机译:树突状细胞控制纤维母细胞网状网​​络张力和淋巴结扩张

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摘要

After immunogenic challenge, infiltrating and dividing lymphocytes markedly increase lymph node cellulaity, leading to organ expansion. Here we report that the physical elasticity of lymph nodes is maintained in part by podoplanin (PDPN) signalling in stromal fibroblastic reticular cells (FRCs) and its modulation by CLEC-2 expressed on dendritic cells. We show in mouse cells that PDPN induces acto-myosin contractility in FRCs via activation of RhoA/C and downstream Rho-associated protein kinase (ROCK). Engagement by CLEC-2 causes PDPN clustering and rapidly uncouples PDPN from RhoA/C activation, relaxing the actomyosin cytoskeleton and pemitting FRC stretching. Notably, administration of CLEC-2 protein to immunized mice augments lymph node expansion. In contrast, lymph node expan-sion is significantly constrained in mice selectively lacking CLEC-2 expression in dendritic cells. Thus, the same dendritic cells that initiate immunity by presenting antigens to T lymphocytes also initiate remoddling of lymph nodes by delivering CLEC-2 to FRCs. CLEC-2 modulation of PDPN signalling permits FRC network stretching and allows for the rapid lymph node expansion-driven by lymphocyte influx and proliferation-that is the critical hallmark of adaptive immunity.%淋巴结是动态结构,它们必须对由局部炎症引发的大量细胞涌入迅速做出反应。然而,淋巴结基质腔室是怎样反应来适应淋巴结膨胀的仍不清楚。这项研究显示,淋巴结基质腔室能通过放松成纤维网状细胞的细胞骨架、允许这些细胞伸展和淋巴结膨胀来容留大量渗透的淋巴细胞。这种淋巴结重塑反应是由进来的、能够呈现抗原的树状细胞上的CLEC-2蛋白与成纤维网状细胞上的"平足蛋白"(podoplanin)的相互作用驱动的。
机译:免疫原性攻击后,浸润和分裂的淋巴细胞显着增加淋巴结的纤维素含量,导致器官扩张。在这里我们报告淋巴结的物理弹性部分维持由在基质成纤维网状细胞(FRCs)中的podoplanin(PDPN)信号传导和由树突状细胞上表达的CLEC-2调节。我们在小鼠细胞中显示PDPN通过激活RhoA / C和下游Rho相关蛋白激酶(ROCK)诱导FRC中的肌动球蛋白收缩。 CLEC-2的参与会导致PDPN聚集,并使PDPN与RhoA / C激活迅速脱钩,从而放宽了放线菌素的细胞骨架并实现了FRC伸展。值得注意的是,将CLEC-2蛋白给予免疫小鼠会增加淋巴结的扩增。相比之下,在树突状细胞中选择性缺乏CLEC-2表达的小鼠中,淋巴结扩张受到明显限制。因此,通过将抗原呈递给T淋巴细胞而启动免疫力的相同树突状细胞也通过将CLEC-2传递至FRCs而引发了淋巴结的重塑。 PDPN信号的CLEC-2调节允许FRC网络伸展,并允许由淋巴细胞流入和增殖驱动的快速淋巴结扩张-这是适应性免疫的关键标志。研究表明,淋巴结基质腔室能通过放松成纤维网状细胞的细胞骨架,允许这些。这种淋巴结重塑反应是由进来的,能够呈现抗原的树状细胞上的CLEC-2蛋白与成纤维网状细胞上的“平足蛋白”。 (podoplanin)的相互作用驱动的。

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  • 来源
    《Nature》 |2014年第7523期|498-502B2|共6页
  • 作者单位

    Immunobiology Laboratory,Cancer Research UK London Research Institute,44 Lincoln's Inn Fields,London WC2A 3LY,UK,Department of Cell and Developmental Eiology,University College London,Gower Street, London WC1E 6BT, UK;

    Immunobiology Laboratory,Cancer Research UK London Research Institute,44 Lincoln's Inn Fields,London WC2A 3LY,UK,Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A3LY, UK;

    Department of Cancer Immunology and AIDS,Dana-Farber Cancer Institute,Boston,Massachusetts 02215,USA;

    Immunobiology Laboratory,Cancer Research UK London Research Institute,44 Lincoln's Inn Fields,London WC2A 3LY,UK,Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA;

    Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A3LY, UK;

    Expermental Histopathology Laboratory,Cancer Research UK London Research Institute,44 Lincoln's Inn Fields,London WC2A 3LY,UK;

    Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A3LY, UK;

    Immunobiology Laboratory,Cancer Research UK London Research Institute,44 Lincoln's Inn Fields,London WC2A 3LY,UK;

    Immunobiology Laboratory,Cancer Research UK London Research Institute,44 Lincoln's Inn Fields,London WC2A 3LY,UK;

    Immunobiology Laboratory,Cancer Research UK London Research Institute,44 Lincoln's Inn Fields,London WC2A 3LY,UK;

    Transgenics Laboratory,Cancer Research UK London Reasearch Institute,Clare Hall Laboratories,South Mimms,Potters Bar,Hertfordshire EN6 3Ld,UK;

    Instituto Gulbenkian de Ciencia,Rua da Quinta Grande 6,2780-156 Oeiras, Portugal,Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal;

    Expermental Histopathology Laboratory,Cancer Research UK London Research Institute,44 Lincoln's Inn Fields,London WC2A 3LY,UK;

    Department of Cancer Immunology, Genentech, One DNA Way, South San Francisco, California 94080, USA;

    Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A3LY, UK;

    Immunobiology Laboratory,Cancer Research UK London Research Institute,44 Lincoln's Inn Fields,London WC2A 3LY,UK;

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