T cell surface redox levels determine T cell reactivity and arthritis susceptibility
T cell surface redox levels determine T cell reactivity and arthritis susceptibility
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DOI：
10.1073/pnas.0604571103
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发表时间：
2006-08-22
影响因子：
11.1
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
由于Ncfl基因（编码中性粒细胞胞质因子1）的等位基因多态性，大鼠和小鼠产生活性氧（ROS）的能力较低，更容易患上严重的关节炎。这些数据表明活性氧参与调节免疫反应。我们现在表明，产生ROS的能力较低与T细胞膜表面上减少的巯基（-SH）数量增加有关。通过谷胱甘肽治疗，人为地增加具有关节炎保护性Ncf1等位基因的动物T细胞上的还原性硫醇的数量，降低了T细胞反应性的阈值，增强了体外和体内的增殖反应。重要的是，具有E3来源的Ncf1等位基因的免疫同源大鼠（DA.Ncf1（E3）大鼠）的T细胞不能将关节炎转移到具有关节炎相关的黑鼠（DA）来源的突变Ncf1等位基因的大鼠（DA.Ncf1（DA）大鼠），在增加细胞表面硫醇水平后，T细胞成为关节炎源性细胞。这一发现被反向实验证实，在该实验中，来自DA的T细胞被氧化。与对照组相比，Ncf1（DA）大鼠诱导的关节炎较轻。因此，我们得出结论，Ncf1控制的ROS产生在调节T细胞表面氧化还原水平中很重要，从而抑制自身反应性和关节炎的发展。
Rats and mice with a lower capacity to produce reactive oxygen species (ROS) because of allelic polymorphisms in the Ncfl gene (which encodes neutrophil cytosolic factor 1) are more susceptible to develop severe arthritis. These data suggest that ROS are involved in regulating the immune response. We now show that the lower capacity to produce ROS is associated with an increased number of reduced thiol groups (-SH) on T cell membrane surfaces. Artificially increasing the number of reduced thiols on T cells from animals with arthritis-protective Ncf1 alleles by glutathione treatment lowered the threshold for T cell reactivity and enhanced proliferative responses in vitro and in vivo. Importantly, T cells from immunized congenic rats with an E3-derived Ncfl allele (DA.Ncf1(E3) rats) that cannot transfer arthritis to rats with an arthritis-associated Dark Agouti (DA)-derived mutated Ncf1 allele (DA.Ncf1(DA) rats) became arthritogenic after increasing cell surface thiol levels. This finding was confirmed by the reverse experiment, in which oxidized T cells from DA.Ncf1(DA) rats induced less severe arthritis compared with controls. Therefore, we conclude that ROS production as controlled by Ncf1 is important in regulating surface redox levels of T cells and thereby suppresses autoreactivity and arthritis development.