Grajewski Rafael S, Silver Phyllis B, Agarwal Rajeev K, Su Shao-Bo, Chan Chi-Chao, Liou Gregory I, Caspi Rachel R
Laboratory of Immunology, National Eye Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
J Exp Med. 2006 Apr 17;203(4):851-6. doi: 10.1084/jem.20050429. Epub 2006 Apr 3.
Susceptibility to experimental autoimmune uveitis (EAU), a model for human uveitis induced in mice with the retinal antigen interphotoreceptor retinoid-binding protein (IRBP), is controlled by "natural" CD4+CD25+ regulatory T (T reg) cells. To examine whether endogenous expression of IRBP is necessary to generate these T reg cells, we studied responses of IRBP knockout (KO) versus wild-type (WT) mice. Unexpectedly, not only WT but also IRBP KO mice immunized with a uveitogenic regimen of IRBP in complete Freund's adjuvant (CFA) exhibited CD25+ regulatory cells that could be depleted by PC61 treatment, which suppressed development of uveitogenic effector T cells and decreased immunological responses to IRBP. These EAU-relevant T reg cells were not IRBP specific, as their activity was not present in IRBP KO mice immunized with IRBP in incomplete Freund's adjuvant (IFA), lacking mycobacteria (whereas the same mice exhibited normal T reg cell activity to retinal arrestin in IFA). We propose that mycobacterial components in CFA activate T reg cells of other specificities to inhibit generation of IRBP-specific effector T cells in a bystander fashion, indicating that effective T reg cells can be antigen nonspecific. Our data also provide the first evidence that generation of specific T reg cells to a native autoantigen in a mouse with a diverse T cell repertoire requires a cognate interaction.
实验性自身免疫性葡萄膜炎（EAU）是一种用视网膜抗原光感受器间维生素A结合蛋白（IRBP）在小鼠中诱导的人类葡萄膜炎模型，其易感性受“天然”CD4 + CD25 +调节性T（Treg）细胞控制。为了研究IRBP的内源性表达对于产生这些Treg细胞是否必要，我们研究了IRBP基因敲除（KO）小鼠与野生型（WT）小鼠的反应。出乎意料的是，不仅WT小鼠，而且用IRBP在完全弗氏佐剂（CFA）中的致葡萄膜炎方案免疫的IRBP KO小鼠也表现出可被PC61处理耗尽的CD25 +调节细胞，这抑制了致葡萄膜炎效应T细胞的发育并降低了对IRBP的免疫反应。这些与EAU相关的Treg细胞不是IRBP特异性的，因为在用缺乏分枝杆菌（而相同小鼠在不含分枝杆菌的不完全弗氏佐剂（IFA）中对视网膜抑制蛋白表现出正常的Treg细胞活性）的不完全弗氏佐剂（IFA）中用IRBP免疫的IRBP KO小鼠中不存在它们的活性。我们提出，CFA中的分枝杆菌成分以旁观者方式激活其他特异性的Treg细胞，以抑制IRBP特异性效应T细胞的产生，这表明有效的Treg细胞可以是抗原非特异性的。我们的数据还提供了第一个证据，即在具有多样化T细胞库的小鼠中，针对天然自身抗原产生特异性Treg细胞需要同源相互作用。
