Institute of Molecular Medicine, Department of Neurobiology Research, University of Southern Denmark, J.B. Winsløwsvej 25, DK-5000 Odense C, Denmark.
Centre d'Immunologie de Marseille-Luminy - CIML, Institut National de la Santé et de la Recherche Médicale, U1104, Centre National de la Recherche Scientifique, UMR7280 and Aix Marseille Université, UM2, F-13009 Marseille, France.
J Autoimmun. 2014 Dec;55:73-85. doi: 10.1016/j.jaut.2014.07.004. Epub 2014 Aug 14.
Thymic epithelial cells (TEC) and dendritic cells (DC) play a role in T cell development by controlling the selection of the T cell receptor repertoire. DC have been described to take up antigens in the periphery and migrate into the thymus where they mediate tolerance via deletion of autoreactive T cells, or by induction of natural regulatory T cells. Migration of DC to thymus is driven by chemokine receptors. CCL2, a major ligand for the chemokine receptor CCR2, is an inflammation-associated chemokine that induces the recruitment of immune cells in tissues. CCL2 and CCR2 are implicated in promoting experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. We here show that CCL2 is constitutively expressed by endothelial cells and TEC in the thymus. Transgenic mice overexpressing CCL2 in the thymus showed an increased number of thymic plasmacytoid DC and pronounced impairment of T cell development. Consequently, CCL2 transgenic mice were resistant to EAE. These findings demonstrate that expression of CCL2 in thymus regulates DC homeostasis and controls development of autoreactive T cells, thus preventing development of autoimmune diseases.
胸腺上皮细胞（TEC）和树突状细胞（DC）通过控制 T 细胞受体库的选择在 T 细胞发育中发挥作用。已经描述了 DC 在周围组织中摄取抗原并迁移到胸腺中，在那里通过删除自身反应性 T 细胞或诱导天然调节性 T 细胞来介导耐受。DC 向胸腺的迁移由趋化因子受体驱动。CCL2 是趋化因子受体 CCR2 的主要配体，是一种与炎症相关的趋化因子，可诱导组织中免疫细胞的募集。CCL2 和 CCR2 参与促进实验性自身免疫性脑脊髓炎（EAE），即多发性硬化症的小鼠模型。我们在这里表明，CCL2 在胸腺中的内皮细胞和 TEC 中持续表达。在胸腺中过表达 CCL2 的转基因小鼠表现出更多的胸腺浆细胞样树突状细胞和明显的 T 细胞发育受损。因此，CCL2 转基因小鼠对 EAE 具有抗性。这些发现表明，胸腺中 CCL2 的表达调节 DC 稳态并控制自身反应性 T 细胞的发育，从而防止自身免疫性疾病的发展。
