Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species
Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species
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DOI：
10.1172/jci31935
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发表时间：
2007-10-01
影响因子：
15.9
通讯作者：
Holmdahl, Rikard
中科院分区：
文献类型：
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作者：
Gelderman, Kyra A.;Hultqvist, Malin;Holmdahl, Rikard
在中性粒细胞胞浆因子1 (Ncf1) （p47phox）多态性的小鼠和大鼠中，产生ROS的能力降低会增加T细胞依赖性关节炎的严重程度。由于T细胞不能发挥氧化破裂，我们假设T细胞的反应性被apc产生的ROS下调。巨噬细胞在apc中具有最高的爆发能力，因此为了研究巨噬细胞ROS对T细胞活化的影响，我们建立了表达功能性Ncf1的转基因小鼠，限定于巨噬细胞。在胶原诱导的关节炎模型中，巨噬细胞限制功能性Ncf1的表达将关节炎抵抗恢复到野生型小鼠的水平，但在T细胞非依赖性抗胶原抗体诱导的关节炎模型中则没有。在转基因小鼠中，T细胞激活下调并向Th2倾斜。在体外，无论T细胞来源如何，巨噬细胞ROS都能抑制IL-2的产生和T细胞的增殖。然而，ifn - γ的产生与巨噬细胞ROS无关，但依赖于T细胞来源。这些作用是抗原依赖性的，但并不局限于II型胶原。综上所述，巨噬细胞来源的ROS在T细胞的选择、成熟和分化中起作用，同时在T细胞活化中起抑制作用，从而介导对关节炎等自身免疫性疾病的保护作用。
Reduced capacity to produce ROS increases the severity of T cell-dependent arthritis in both mice and rats with polymorphisms in neutrophil cytosolic factor 1 (Ncf1) (p47phox). Since T cells cannot exert oxidative burst, we hypothesized that T cell responsiveness is downregulated by ROS produced by APCs. Macrophages have the highest burst capacity among APCs, so to study the effect of macrophage ROS on T cell activation, we developed transgenic mice expressing functional Ncf1 restricted to macrophages. Macrophage-restricted expression of functional Ncf1 restored arthritis resistance to the level of that of wild-type mice in a collagen-induced arthritis model but not in a T cell-independent anti-collagen antibody-induced arthritis model. T cell activation was downregulated and skewed toward Th2 in transgenic mice. In vitro, IL-2 production and T cell proliferation were suppressed by macrophage ROS, irrespective of T cell origin. IFN-gamma production, however, was independent of macrophage ROS but dependent on T cell origin. These effects were antigen dependent but not restricted to collagen type II. In conclusion, macrophage-derived ROS play a role in T cell selection, maturation, and differentiation, and also a suppressive role in T cell activation, and thereby mediate protection against autoimmune diseases like arthritis.