CD8 T Cells Regulate Allergic Contact Dermatitis by Modulating CCR2-Dependent TNF/iNOS-Expressing Ly6C+CD11b+ Monocytic Cells
CD8 T Cells Regulate Allergic Contact Dermatitis by Modulating CCR2-Dependent TNF/iNOS-Expressing Ly6C+CD11b+ Monocytic Cells
复制标题
DOI：
10.1038/jid.2013.403
复制
发表时间：
2014-03-01
影响因子：
6.5
通讯作者：
Kemeny, David M.
中科院分区：
文献类型：
--
作者：
Chong, Shu Zhen;Tan, Kar Wai;Kemeny, David M.
单核细胞及其衍生细胞在炎症和免疫防御中发挥着关键作用。然而，它们在过敏性接触性皮炎等皮肤病中的作用仍不清楚。利用对2,4-二硝基氯苯的接触超敏反应（CHS）模型，我们发现Ly6C（+）CD11b（+）单核细胞参与CHS的病理生理学，并且它们的积累受到效应CD8 T细胞的调节。这些 Ly6C(+)CD11b(+) 单核细胞是肿瘤坏死因子-α (TNF-α) 和诱导型一氧化氮合酶 (iNOS) 的主要贡献者，源自 Ly6C(hi)CCR2(+) 单核细胞，因为它们在非发炎皮肤中不存在，并因 2 型 C-C 趋化因子受体炎症而积累 (CCR2)依赖方式。重要的是，CCR2(-/-) 小鼠或通过氯膦酸盐脂质体去除单核细胞的野生型小鼠显示 TNF-α 和 iNOS 表达显着降低，同时皮肤炎症减轻。利用转基因小鼠和抗体耗竭，我们发现效应CD8 T细胞通过IL-17调节Ly6C(+)CD11b(+)单核细胞的积累，并通过IFN-γ激活它们产生TNF-α和iNOS。 CD8 T 细胞衍生的 IFN-γ 对于表达主要组织相容性复合体 II 的 Ly6C(+)CD11b(+) 子集的积累也至关重要，该子集表达中等水平的 CD11c 和共刺激分子。综上所述，我们的研究结果表明 CD8 T 细胞通过表达 Ly6C(+)CD11b(+) 单核细胞的 TNF/iNOS 调节炎症级联反应，从而进一步深入了解过敏性接触性皮炎的病理生理学。
Monocytes and their derived cells have critical roles in inflammation and immune defense. However, their function in skin diseases such as allergic contact dermatitis remains poorly defined. Using a model of contact hypersensitivity (CHS) toward 2,4-dinitrochlorobenzene, we show that Ly6C(+)CD11b(+) monocytic cells participate in the pathophysiology of CHS and their accumulation is regulated by effector CD8 T cells. These Ly6C(+)CD11b(+) monocytic cells are the primary contributors of tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) and derive from Ly6C(hi)CCR2(+) monocytes, as they were absent in non-inflamed skin and accumulate as a consequence of inflammation in a C-C chemokine receptor type 2 (CCR2) dependent manner. Importantly, CCR2(-/-) mice, or wild-type mice depleted of monocytes via clodronate liposomes, display a marked decrease in TNF-alpha and iNOS expression accompanied by attenuated skin inflammation. Using transgenic mice and antibody depletion, we show that effector CD8 T cells regulate the accumulation of Ly6C(+)CD11b(+) monocytic cells through IL-17 and activate them for TNF-alpha and iNOS through IFN-gamma. CD8 T cell derived IFN-gamma was also critical for the accumulation of the major histocompatibility complex II-expressing Ly6C(+)CD11b(+) subset, which expressed intermediate levels of CD11c and costimulatory molecules. Taken together, our findings provide further insight into the pathophysiology of allergic contact dermatitis by showing that CD8 T cells regulate the inflammatory cascade through TNF/iNOS expressing Ly6C(+)CD11b(+) monocytic cells.