CCL20 and β-Defensin-2 Induce Arrest of Human Th17 Cells on Inflamed Endothelium In Vitro under Flow Conditions
CCL20 and β-Defensin-2 Induce Arrest of Human Th17 Cells on Inflamed Endothelium In Vitro under Flow Conditions
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DOI：
10.4049/jimmunol.1000597
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发表时间：
2011-02-01
影响因子：
4.4
通讯作者：
Pene, Jerome
中科院分区：
文献类型：
--
作者：
Ghannam, Soufiane;Dejou, Cecile;Pene, Jerome
CCR 6是一种趋化因子受体，在Th 17细胞的细胞表面表达，Th 17细胞是分泌IL-17和IL-22的CD 4（+）T细胞群体，具有抗病原体和炎症特性。在目前的研究中，我们已经确定了参与CCR 6在人类Th 17淋巴细胞向炎症组织迁移的能力，通过分析其配体诱导逮捕这些细胞在体外发炎的内皮细胞在流动条件下。我们表明，极化，原位分化，皮肤来源的Th 17克隆激活通过TCR-CD 3复合物产生CCL 20除了IL-17和IL-22。后者细胞因子以协同方式诱导表皮角质形成细胞产生人β-防御素（hBD）-2，但既不诱导hBD-1也不诱导hBD-3。CCL 20和hBD-2都能够以CD 54依赖性方式诱导HUVEC上Th 17细胞的停滞，但不能诱导Th 1或Th 2细胞的停滞，该方式是CCR 6特异性的并且独立于CXCR 4的表达，据报道CXCR 4是hBD-2的替代受体。此外，银特异性激活在转录和蛋白质水平上都会诱导CCR 6表达的短暂丧失，这是以缓慢的动力学发生的，并且不是由于内源性CCL 20介导的CCR 6内化。总之，这些结果表明，Ag特异性激活最初将有助于CCR 6介导的Th 17细胞向发炎组织的运输和隔离，但它最终导致对CCR 6配体进一步刺激这些细胞的无反应性的暂时状态，从而允许它们随后迁移出发炎部位。免疫学杂志，2011，186：1411-1420。
CCR6 is a chemokine receptor that is expressed at the cell surface of Th17 cells, an IL-17 and IL-22 secreting population of CD4(+) T cells with antipathogenic, as well as inflammatory, properties. In the current study, we have determined the involvement of CCR6 in human Th17 lymphocyte migration toward inflamed tissue by analyzing the capacity of its ligands to induce arrest of these cells onto inflamed endothelium in vitro under flow conditions. We show that polarized, in situ-differentiated, skin-derived Th17 clones activated via the TCR-CD3 complex produce CCL20 in addition to IL-17 and IL-22. The latter cytokines induce, in a synergic fashion, the production of human beta-defensin (hBD)-2, but neither hBD-1 nor hBD-3, by epidermal keratinocytes. Both CCL20 and hBD-2 are capable of inducing the arrest of Th17 cells, but not Th1 or Th2 cells, on HUVEC in an CD54-dependent manner that is CCR6 specific and independent from the expression of CXCR4, reported to be an alternative receptor for hBD-2. In addition, Ag-specific activation induces a transient loss of CCR6 expression, both at the transcriptional and protein level, which occurs with slow kinetics and is not due to endogenous CCL20-mediated internalization of CCR6. Together, these results indicate that Ag-specific activation will initially contribute to CCR6-mediated Th17 cell trafficking toward and sequestration in inflamed tissue, but that it eventually results in a transitory state of nonresponsiveness to further stimulation of these cells with CCR6 ligands, thus permitting their subsequent migration out of the inflamed site. The Journal of Immunology, 2011, 186: 1411-1420.