Improvement of Foxp3 stability through CNS2 demethylation by TET enzyme induction and activation.
Improvement of Foxp3 stability through CNS2 demethylation by TET enzyme induction and activation.
复制标题
DOI：
10.1093/intimm/dxx049
复制
发表时间：
2017-08-01
影响因子：
4.4
通讯作者：
Yoshimura A
中科院分区：
文献类型：
--
作者：
Someya K;Nakatsukasa H;Ito M;Kondo T;Tateda KI;Akanuma T;Koya I;Sanosaka T;Kohyama J;Tsukada YI;Takamura-Enya T;Yoshimura A
逆转录病毒TET 1或缺氧使Foxp 3在体外产生的iT细胞中稳定。由于诱导的调节性T细胞（iT细胞）可以在体外大量产生，因此这些细胞预期在临床上可用于诱导各种免疫疾病中的免疫耐受。然而，由于Foxp 3基因座的保守非编码序列2（CNS 2）中缺少CpG岛的去甲基化，Foxp 3（叉头盒P3）在iTcells中的表达是不稳定的。为了促进CNS 2的去甲基化，我们过表达了10 - 11易位（泰特）蛋白的催化结构域（CD），其催化5-甲基胞嘧啶的迭代去甲基化步骤。TET-CD在iT细胞中的过表达导致CNS 2的部分去甲基化和稳定的Foxp 3表达。我们还发现，泰特表达在低氧（5%）培养条件下增强，这有利于CNS 2 DNA去甲基化和Foxp 3表达的稳定，TET 2和TET 3依赖的方式。与维生素C处理（已报道其增强泰特催化活性）组合，与未处理的iTdR相比，在低氧条件下产生的iTdR在体外和体内保持更稳定的Foxp 3表达，并在结肠炎模型中表现出更强的抑制活性。我们的数据表明，诱导和激活的泰特酶在iTlag将是一种有效的方法Treg介导的过继免疫治疗。
Retroviral TET1 or hypoxia stabilize Foxp3 in iTregs generated in vitro Since induced regulatory T cells (iTregs) can be produced in a large quantity in vitro, these cells are expected to be clinically useful to induce immunological tolerance in various immunological diseases. Foxp3 (Forkhead box P3) expression in iTregs is, however, unstable due to the lack of demethylation of the CpG island in the conserved non-coding sequence 2 (CNS2) of the Foxp3 locus. To facilitate the demethylation of CNS2, we over-expressed the catalytic domain (CD) of the ten-eleven translocation (TET) protein, which catalyzes the steps of the iterative demethylation of 5-methylcytosine. TET-CD over-expression in iTregs resulted in partial demethylation of CNS2 and stable Foxp3 expression. We also discovered that TET expression was enhanced under low oxygen (5%) culture conditions, which facilitated CNS2 DNA demethylation and stabilization of Foxp3 expression in a TET2- and TET3-dependent manner. In combination with vitamin C treatment, which has been reported to enhance TET catalytic activity, iTregs generated under low oxygen conditions retained more stable Foxp3 expression in vitro and in vivo and exhibited stronger suppression activity in a colitis model compared with untreated iTregs. Our data indicate that the induction and activation of TET enzymes in iTregs would be an effective method for Treg-mediated adoptive immunotherapy.
登录
查看更多内容
控制FOXP3基因座中的顺式元素对调节T细胞身份的遗传控制。
影响因子：
64.5
作者：
Feng Y;Arvey A;Chinen T;van der Veeken J;Gasteiger G;Rudensky AY
通讯作者：
Rudensky AY
影响因子：
50.3
作者：
Moran-Crusio K;Reavie L;Shih A;Abdel-Wahab O;Ndiaye-Lobry D;Lobry C;Figueroa ME;Vasanthakumar A;Patel J;Zhao X;Perna F;Pandey S;Madzo J;Song C;Dai Q;He C;Ibrahim S;Beran M;Zavadil J;Nimer SD;Melnick A;Godley LA;Aifantis I;Levine RL
通讯作者：
Levine RL
影响因子：
8.8
作者：
Mariani CJ;Vasanthakumar A;Madzo J;Yesilkanal A;Bhagat T;Yu Y;Bhattacharyya S;Wenger RH;Cohn SL;Nanduri J;Verma A;Prabhakar NR;Godley LA
通讯作者：
Godley LA
DOI：
10.1073/pnas.0811556106
发表时间：
2009-02-10
影响因子：
11.1
作者：
Komatsu, Noriko;Mariotti-Ferrandiz, Maria Encarnita;Hori, Shohei
通讯作者：
Hori, Shohei
DOI：
10.4049/jimmunol.1100061
发表时间：
2011-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chen Q;Kim YC;Laurence A;Punkosdy GA;Shevach EM
通讯作者：
Shevach EM