IκBNS Protein Mediates Regulatory T Cell Development via Induction of the Foxp3 Transcription Factor
IκBNS Protein Mediates Regulatory T Cell Development via Induction of the Foxp3 Transcription Factor
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DOI：
10.1016/j.immuni.2012.08.023
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发表时间：
2012-12-14
期刊：
影响因子：
32.4
通讯作者：
Schmitz, Ingo
中科院分区：
文献类型：
--
作者：
Schuster, Marc;Glauben, Rainer;Schmitz, Ingo
叉头盒P3阳性（Foxp 3（+））调节性T（Treg）细胞抑制免疫应答并调节外周耐受性。在这里，我们表明，非典型抑制剂NF κ B（I κ B）I κ B-NS驱动Foxp 3的表达，通过与启动子和保守的非编码序列3（CNS 3）的Foxp 3基因座。因此，I κ B-NS缺乏导致体内Foxp 3 + Treg细胞的大量减少和体外转化生长因子-β（TGF-13）处理后Foxp 3诱导受损。此外，更少的Foxp 3 + Treg细胞从I κ B-NS缺陷型CD 25（-）CD 4（+）T细胞过继转移到免疫缺陷型受体中。重要的是，I κ B-NS是未成熟的GITR（+）CD 25（+）Foxp 3（-）胸腺Treg细胞前体向Foxp 3（+）细胞转化所必需的。与缺乏c-Rel或Carmal的小鼠相反，I κ B-NS缺陷小鼠不显示减少的Treg前体细胞。我们的研究结果表明，IkBN在胸腺和肠道炎症期间严格调节Treg细胞发育，表明靶向IkBN的策略可以调节Treg细胞区室。
Forkhead box P3 positive (Foxp3(+)) regulatory T (Treg) cells suppress immune responses and regulate peripheral tolerance. Here we show that the atypical inhibitor of NF kappa B (I kappa B) I kappa B-NS drives Foxp3 expression via association with the promoter and the conserved noncoding sequence 3 (CNS3) of the Foxp3 locus. Consequently, I kappa B-NS deficiency leads to a substantial reduction of Foxp3+ Treg cells in vivo and impaired Foxp3 induction upon transforming growth factor-beta (TGF-13) treatment in vitro. Moreover, fewer Foxp3+ Treg cells developed from I kappa B-NS-deficient CD25(-)CD4(+) T cells adoptively transferred into immunodeficient recipients. Importantly, I kappa B-NS was required for the transition of immature GITR(+)CD25(+) Foxp3(-) thymic Treg cell precursors into Foxp3(+) cells. In contrast to mice lacking c-Rel or Carmal, I kappa B-NS-deficient mice do not show reduced Treg precursor cells. Our results demonstrate that IkBNs critically regulates Treg cell development in the thymus and during gut inflammation, indicating that strategies targeting IkBNs could modulate the Treg cell compartment.