Yabe Rikio, Shimizu Kenji, Shimizu Soichiro, Azechi Satoe, Choi Byung-Il, Sudo Katsuko, Kubo Sachiko, Nakae Susumu, Ishigame Harumichi, Kakuta Shigeru, Iwakura Yoichiro
Center for Animal Disease Models, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Noda, Chiba 278-0022, Japan Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, University of Tokyo (IMSUT), Minato-ku, Tokyo 108-8639, Japan Medical Mycology Research Center, Chiba University, Inohana Chuo-ku, Chiba 260-8673, Japan.
Center for Animal Disease Models, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Noda, Chiba 278-0022, Japan Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, University of Tokyo (IMSUT), Minato-ku, Tokyo 108-8639, Japan.
Int Immunol. 2015 Apr;27(4):169-81. doi: 10.1093/intimm/dxu098. Epub 2014 Oct 25.
Allergic contact dermatitis (ACD) is a typical occupational disease in industrialized countries. Although various cytokines and chemokines are suggested to be involved in the pathogenesis of ACD, the roles of these molecules remain to be elucidated. CC chemokine receptor 8 (CCR8) is one such molecule, of which expression is up-regulated in inflammatory sites of ACD patients. In this study, we found that Ccr8(-/-) mice developed severer contact hypersensitivity (CHS) responses to 2,4-dinitrofluorobenzene, a murine model of ACD, compared with wild-type mice. T cells from Ccr8(-/-) mice showed enhanced proliferative recall responses and Th1 and Th17 cell populations were expanded in these mice. However, CHS responses were similar between SCID mice adoptively transferred with Ccr8(-/-) and wild-type T cells, suggesting that CCR8 in T cells is not responsible for the exacerbation of CHS. Notably, skin-resident dendritic cells (DCs), such as Langerhans cells and dermal DCs, and inflammatory DCs were highly accumulated in lymph nodes (LNs) of Ccr8(-/-) mice after sensitization. Consistent with this, Ccr8(-/-) antigen-presenting cells readily migrated from the skin to the draining LNs after sensitization. These observations suggest that CCR8 negatively regulates migration of cutaneous DCs from the skin to the draining LNs in CHS by keeping these cells in the skin.
过敏性接触性皮炎（ACD）在工业化国家是一种典型的职业病。尽管多种细胞因子和趋化因子被认为参与了ACD的发病机制，但这些分子的作用仍有待阐明。CC趋化因子受体8（CCR8）就是这样一种分子，其在ACD患者的炎症部位表达上调。在本研究中，我们发现与野生型小鼠相比，Ccr8基因敲除（Ccr8(-/-)）小鼠对2,4-二硝基氟苯（一种ACD的小鼠模型）产生了更严重的接触性超敏反应（CHS）。Ccr8(-/-)小鼠的T细胞表现出增强的增殖回忆反应，并且这些小鼠中的Th1和Th17细胞群体有所扩大。然而，用Ccr8(-/-)和野生型T细胞过继转移后的严重联合免疫缺陷（SCID）小鼠之间的CHS反应相似，这表明T细胞中的CCR8与CHS的加重无关。值得注意的是，致敏后，皮肤驻留树突状细胞（DC），如朗格汉斯细胞和真皮DC，以及炎性DC在Ccr8(-/-)小鼠的淋巴结（LN）中高度聚集。与此一致的是，致敏后Ccr8(-/-)抗原呈递细胞很容易从皮肤迁移到引流淋巴结。这些观察结果表明，CCR8通过将皮肤DC保留在皮肤中，对CHS中皮肤DC从皮肤向引流淋巴结的迁移起负向调节作用。
