Peripherally Induced Treg: Mode, Stability, and Role in Specific Tolerance
Peripherally Induced Treg: Mode, Stability, and Role in Specific Tolerance
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DOI：
10.1007/s10875-008-9254-8
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发表时间：
2008-11-01
影响因子：
9.1
通讯作者：
von Boehmer, Harald
中科院分区：
文献类型：
--
作者：
Apostolou, Irina;Verginis, Panos;von Boehmer, Harald
表达Foxp 3的调节性T细胞（Treg）在人和小鼠中具有预防自身免疫性疾病的重要功能。Foxp 3与约1,100个基因的叉头基序结合，并且结合强度在佛波醇12-肉豆蔻酸酯13-乙酸酯/离子霉素刺激后增加。在表达Foxp 3的T细胞杂交瘤中，Foxp 3启动子结合不导致基因的激活或抑制，其仅在T细胞激活后可见。这些发现与其他人的观察结果一致，即Foxp 3与DNA结合复合物中的T细胞受体（TCR）依赖性转录因子协作发挥重要功能。当发育中的T细胞在胸腺中遇到TCR激动剂配体时，可以产生TCR。这个过程显然依赖于共刺激信号。相反。初始T细胞向TcB的胸腺外转化似乎依赖于转化生长因子（TGF）-β，并被共刺激抑制。事实上，树突状细胞衍生的视黄酸通过抵消共刺激的负面影响来帮助转化过程。通过体内亚免疫原性抗原递送诱导的TcB比在体外存在TGF-β的情况下通过抗原刺激诱导的TcB稳定得多，这与Foxp 3基因座的去甲基化程度相关。T细胞活化可以通过抗原特异性T细胞的转化来诱导，这种转化在野生型小鼠中以非常低的频率发生。通过HY抗原的单一肽将幼稚分化簇（CD）4 T细胞转化为TcB，导致当与男性皮肤或造血移植物一起呈递时，对由CD 4以及CD 8 T细胞识别的整组HY表位的完全抗原特异性耐受。
Foxp3-expressing regulatory T cells (Treg) have an essential function of preventing autoimmune disease in man and mouse. Foxp3 binds to forkhead motifs of about 1,100 genes and the strength of binding increases upon phorbol 12-myristate 13-acetate/ionomycin stimulation. In Foxp3-expressing T cell hybridomas, Foxp3 promoter binding does not lead to activation or suppression of genes which becomes only visible after T cell activation. These findings are in line with observations by others that Foxp3 exerts important functions in collaboration with T cell receptor (TCR)-dependent transcription factors in a DNA-binding complex. Tregs can be generated when developing T cells encounter TCR agonist ligands in the thymus. This process apparently depends on costimulatory signals. In contrast. extrathymic conversion of naive T cells into Tregs appears to depend on transforming growth factor (TGF)-beta and is inhibited by costimulation. In fact, dendritic cell-derived retinoic acid helps the conversion process by counteracting the negative impact of costimulation. Tregs induced by subimmunogenic antigen delivery in vivo are much more stable than Tregs induced by antigenic stimulation in the presence of TGF-beta in vitro which correlates with the extent of demethylation of the Foxp3 locus. Tregs can be induced by conversion of antigen-specific T cells that occur with a very low frequency in wt mice. Conversion of naive cluster of differentiation (CD)4 T cells into Tregs by a single peptide of HY antigens results in complete antigen-specific tolerance to an entire set of HY epitopes recognized by CD4 as well as CD8 T cells when presented with male skin or hemopoietic grafts.