Lügering Andreas, Floer Martin, Westphal Sabine, Maaser Christian, Spahn Thomas W, Schmidt M Alexander, Domschke Wolfram, Williams Ifor R, Kucharzik Torsten
Department of Medicine B, University of Münster, Albert-Schweitzer-Strasse 33, D-48129 Münster, Germany.
Am J Pathol. 2005 Jun;166(6):1647-54. doi: 10.1016/S0002-9440(10)62475-3.
The chemokine Mip3alpha is specifically expressed by the follicle-associated epithelia (FAE) covering intestinal Peyer's patches (PPs) and is the only known chemokine ligand for the chemokine receptor CCR6. Although CCR6-deficient mice are known to have a perturbed intestinal immune system, little is known about the specific impact of this interaction for Peyer's patch formation. To elucidate the effect of Mip3alpha on PP lymphocyte development, we used a CCR6/enhanced green fluorescent protein (EGFP) knock-in mouse model and analyzed lymphocyte development by immunohistochemistry and flow cytometry. PPs of CCR6-/- mice were significantly size-reduced with a proportional loss of B cells and T cells, whereas T-cell subsets were disturbed with a decreased CD4/CD8 ratio paralleled with a loss of regulatory CD4+ CD45Rb(low) T cells. The analysis of cytokine production by CCR6-expressing cells could demonstrate that CCR6 is involved in the regulation of cytokine secretion such as interleukin-12 by dendritic cells. Quantification of UEA-1+ cells inside the FAE showed reduced M-cell numbers in CCR6-deficient mice. These results suggest that the interaction of CCR6 with its ligand Mip3alpha is important for immune responses generated inside the PPs, particularly for the generation of regulatory CD4+ T cells residing inside PPs and for the formation of M cells.
趋化因子Mip3alpha由覆盖肠道派尔集合淋巴结（PPs）的滤泡相关上皮（FAE）特异性表达，并且是趋化因子受体CCR6唯一已知的趋化因子配体。尽管已知CCR6缺陷型小鼠的肠道免疫系统紊乱，但对于这种相互作用对派尔集合淋巴结形成的具体影响知之甚少。为了阐明Mip3alpha对PP淋巴细胞发育的影响，我们使用了CCR6/增强型绿色荧光蛋白（EGFP）基因敲入小鼠模型，并通过免疫组织化学和流式细胞术分析淋巴细胞发育。CCR6 - / - 小鼠的PPs明显变小，B细胞和T细胞成比例减少，而T细胞亚群受到干扰，CD4/CD8比率降低，同时调节性CD4 + CD45Rb（低）T细胞减少。对表达CCR6的细胞产生细胞因子的分析表明，CCR6参与树突状细胞等细胞因子分泌的调节，如白细胞介素-12。对FAE内UEA-1 +细胞的定量分析显示CCR6缺陷型小鼠的M细胞数量减少。这些结果表明，CCR6与其配体Mip3alpha的相互作用对于PPs内产生的免疫反应很重要，特别是对于驻留在PPs内的调节性CD4 + T细胞的产生以及M细胞的形成。
