Yu Di, Tan Andy Hee-Meng, Hu Xin, Athanasopoulos Vicki, Simpson Nicholas, Silva Diego G, Hutloff Andreas, Giles Keith M, Leedman Peter J, Lam Kong Peng, Goodnow Christopher C, Vinuesa Carola G
Division of Immunology and Genetics, John Curtin School of Medical Research, The Australian National University, Canberra, 2601, Australia.
Nature. 2007 Nov 8;450(7167):299-303. doi: 10.1038/nature06253.
Immune responses are normally targeted against microbial pathogens and not self-antigens by mechanisms that are only partly understood. Here we define a newly discovered pathway that prevents autoimmunity by limiting the levels on T lymphocytes of aco-stimulatory receptor, the inducible T-cell co-stimulator(ICOS). In sanroque mice homozygous for an M199R mutation in the ROQ domain of Roquin (also known as Rc3h1), increased Icos expression on T cells causes the accumulation of lymphocytes that is associated with a lupus-like autoimmune syndrome. Roquin normally limits Icos expression by promoting the degradation of Icos messenger RNA.A conserved segment in the unusually long ICOS 3' untranslated mRNA is essential for regulation by Roquin. This segment comprises a 47-base-pair minimal region complementary to T-cell-expressed microRNAs including miR-101, the repressive activity of which is disrupted by base-pair inversions predicted to abrogate miR-101 binding. These findings illuminate a critical post-transcriptional pathway within T cells that regulates lymphocyte accumulation and autoimmunity, and highlights the therapeutic potential of partially antagonising the ICOS pathway.
免疫反应通常通过一些仅被部分理解的机制靶向微生物病原体而非自身抗原。在此，我们定义了一条新发现的途径，该途径通过限制共刺激受体——诱导性T细胞共刺激分子（ICOS）在T淋巴细胞上的水平来预防自身免疫。在Roquin（也称为Rc3h1）的ROQ结构域中存在M199R突变的纯合子sanroque小鼠中，T细胞上ICOS表达的增加导致淋巴细胞聚集，这与狼疮样自身免疫综合征相关。Roquin通常通过促进ICOS信使RNA的降解来限制ICOS的表达。ICOS异常长的3'非翻译mRNA中的一个保守片段对于Roquin的调控至关重要。该片段包含一个47个碱基对的最小区域，与T细胞表达的微小RNA（包括miR-101）互补，预测碱基对倒置会消除miR-101结合，从而破坏其抑制活性，并干扰其抑制活性。这些发现揭示了T细胞内一条关键的转录后途径，该途径调节淋巴细胞聚集和自身免疫，并突出了部分拮抗ICOS途径的治疗潜力。
