CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion
CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion
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DOI：
10.1084/jem.20040179
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发表时间：
2004-06-07
影响因子：
15.3
通讯作者：
Benoist, C
中科院分区：
文献类型：
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作者：
Herman, AE;Freeman, GJ;Benoist, C
CD4(+)CD25(+)调节性T细胞（Tregs）可预防自身免疫性疾病，但对于它们在自发性自身免疫疾病中自然发挥作用的确切位置却知之甚少。在此，我们报道在1型糖尿病发病前，调节性T细胞和效应性T细胞（Teffs）在胰腺病变部位共存。我们发现BDC2.5 T细胞受体转基因动物的胰腺中含有一小部分FoxP3阳性的CD4(+)CD25(+)CD69(-)细胞，这些细胞处于活跃的更新状态，表达克隆型受体，并具有功能性调节活性。基因表达谱分析证实，胰腺组织中的CD4(+)CD25(+)CD69(-)细胞表达可用于诊断调节性细胞的转录本，但白细胞介素10和可诱导共刺激分子（ICOS）的水平明显高于其在淋巴结中的对应细胞。阻断ICOS可迅速使早期胰岛炎转变为糖尿病，这打破了效应性T细胞和调节性T细胞的平衡，并促使调节性T细胞特异性基因表达谱发生非常广泛的改变。因此，CD4(+)CD25(+)CD69(-)调节性T细胞直接在自身免疫病变部位发挥作用，并且依赖ICOS使其保持在非破坏性状态。
CD4(+) CD25(+) T regulatory cells (Tregs) prevent autoimmune disease, yet little is known about precisely where they exert their influence naturally in a spontaneous autoimmune disorder. Here, we report that Tregs and T effector cells (Teffs) coexist within the pancreatic lesion before type 1 diabetes onset. We find that BDC2.5 T cell receptor transgenic animals contain a small subset of FoxP3 positive CD4(+) CD25(+) CD69(-) cells in the pancreas, actively turning over, expressing the clonotypic receptor, and containing functional regulatory activity. Gene expression profiling confirms that the CD4(+) CD25(+) CD69(-) cells in pancreatic tissue express transcripts diagnostic of regulatory cells, but with significantly higher levels of interleukin 10 and inducible costimulator (ICOS) than their lymph node counterparts. Blockade of ICOS rapidly converts early insulitis to diabetes, which disrupts the balance of Teffs and Tregs and promotes a very broad shift in the expression of the T regulatory-specific profile. Thus, CD4(+) CD25(+) 69(-) Tregs operate directly in the autoimmune lesion and are dependent on ICOS to keep it in a nondestructive state.