Inhibition of CCR6 Function Reduces the Severity of Experimental Autoimmune Encephalomyelitis via Effects on the Priming Phase of the Immune Response
Inhibition of CCR6 Function Reduces the Severity of Experimental Autoimmune Encephalomyelitis via Effects on the Priming Phase of the Immune Response
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DOI：
10.4049/jimmunol.0713169
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发表时间：
2009-03-01
影响因子：
4.4
通讯作者：
McColl, Shaun R.
中科院分区：
文献类型：
--
作者：
Liston, Adrian;Kohler, Rachel E.;McColl, Shaun R.
趋化因子对于免疫系统的稳态和激活至关重要。趋化因子配体/受体配对 CCL20/CCR6 很有趣，因为这些分子表现出稳态和激活功能的特征。这些双重特征表明 CCR6 在免疫反应的启动阶段和效应阶段发挥着重要作用。然而，虽然 CCR6 在多个模型中与效应器阶段有关，但在启动阶段的作用尚不清楚。在此，我们分析了 CCR6 在实验性自身免疫性脑脊髓炎 (EAE) 期间免疫反应的这两个重要方面的作用。 EAE期间，CCR6及其趋化因子配体CCL20在引流淋巴结和脊髓中上调，并且CCR6在EAE诱导后分裂的CD4(+)T细胞上上调。这种表达的功能作用通过基因靶向 CCR6 缺陷小鼠和用中和性抗 CCR6 Ab 或新型受体拮抗剂治疗的小鼠中 EAE 发育受损得到证实。 EAE 的抑制是由于自身反应性 CD4(+) T 细胞的启动减少，这可能是由于树突状细胞后期流入引流淋巴结受损所致。这伴随着从淋巴结流出的活化淋巴细胞的减少。这些结果证明了 CCR6 在自身反应性淋巴细胞启动和迁移至传出淋巴管的机制中的新作用。免疫学杂志，2009，182：3121-3130。
Chemokines are essential for homeostasis and activation of the immune system. The chemokine ligand/receptor pairing CCL20/CCR6 is interesting because these molecules display characteristics of both homeostatic and activation functions. These dual characteristics suggest a role for CCR6 in the priming and effector phases of the immune response. However, while CCR6 has been implicated in the effector phase in several models, a role in the priming phase is less clear. Herein we analyze the role of CCR6 in these two important arms of the immune response during experimental autoimmune encephalomyelitis (EAE). Both CCR6 and its chemokine ligand CCL20 were up-regulated in the draining lymph nodes and spinal cord during EAE, and CCR6 was up-regulated on CD4(+) T cells that had divided following induction of EAE. The functional role of this expression was demonstrated by impaired development of EAE in gene-targeted CCR6-deficient mice and in mice treated either with a neutralizing anti-CCR6 Ab or with a novel receptor antagonist. Inhibition Of EAE was due to reduced priming Of autoreactive CD4(+) T cells probably as a result of impaired late-stage influx of dendritic cells into draining lymph nodes. This was accompanied by reduced egress of activated lymphocytes from the lymph nodes. These results demonstrate a novel role for CCR6 in the mechanism of autoreactive lymphocyte priming and emigration to the efferent lymphatics. The Journal of Immunology, 2009, 182: 3121-3130.