Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling.
Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling.
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DOI：
10.1038/ni.3288
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发表时间：
2015-11
影响因子：
30.5
通讯作者：
Chatila TA
中科院分区：
文献类型：
--
作者：
Charbonnier LM;Wang S;Georgiev P;Sefik E;Chatila TA
Notch 受体指导辅助 T 细胞 (TH) 细胞亚群的分化，但它们对调节性 T (Treg) 细胞反应的影响尚不清楚。我们在此报道，Notch 通路成分的谱系特异性删除增强了 Treg 细胞介导的 TH1 反应抑制，并防止其 TH1 偏斜和细胞凋亡。编码Notch1胞内结构域的功能获得性转基因在Treg细胞中的表达导致淋巴细胞增殖，加剧TH1反应和自身免疫。细胞固有的规范Notch信号传导损害Treg细胞的适应性，促进Treg细胞获得TH1细胞样表型，而Rictor依赖性非规范Notch信号传导激活AKT-Foxo1轴并损害Foxp3表观遗传稳定性。这些发现确立了 Notch 信号在控制外周 Treg 细胞功能中的关键作用。
Notch receptors direct the differentiation of T helper (TH) cell subsets, but their influence on regulatory T (Treg) cell responses is obscure. We here report that lineage-specific deletion of components of the Notch pathway enhanced Treg cell-mediated suppression of TH1 responses, and protected against their TH1 skewing and apoptosis. Expression in Treg cells of gain of function transgene encoding Notch1 intracellular domain resulted in lymphoproliferation, exacerbated TH1 responses and autoimmunity. Cell-intrinsic canonical Notch signaling impaired Treg cell fitness, promoted the acquisition by Treg cells of a TH1 cell-like phenotype, whereas Rictor-dependent non-canonical Notch signaling activated the AKT-Foxo1 axis and impaired Foxp3 epigenetic stability. These findings establish a critical role for Notch signaling in controlling peripheral Treg cell functions.