Foxp3-dependent programme of regulatory T-cell differentiation
Foxp3-dependent programme of regulatory T-cell differentiation
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DOI：
10.1038/nature05543
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发表时间：
2007-02-15
期刊：
影响因子：
64.8
通讯作者：
Rudensky, Alexander Y.
中科院分区：
文献类型：
--
作者：
Gavin, Marc A.;Rasmussen, Jeffrey P.;Rudensky, Alexander Y.
调节性CD4(+) T细胞（T - R细胞）的发育严重依赖于X染色体连锁的转录因子Foxp3（叉头框P3），可防止自身破坏性免疫反应(1)。尽管Foxp3具有重要作用，但它赋予T - R前体细胞的分子和功能特征仍然未知。有人提出，Foxp3的表达对于T - R前体细胞的存活以及它们在T细胞受体结合后不能产生白细胞介素（IL）-2和独立增殖都是必需的，这增加了这种“无反应性”与T - R抑制能力密切相关的可能性(2 - 4)。在此，我们通过将依赖于Foxp3的特征与在小鼠中先于其表达并促进其表达的信号所诱导的特征区分开来，发现后一种信号包含T - R细胞的若干功能和转录特征。尽管Foxp3的功能对于T - R细胞的抑制活性是必需的，但在很大程度上，Foxp3放大并固定了T - R细胞预先建立的分子特征，包括无反应性以及对旁分泌IL - 2的依赖性。此外，Foxp3通过修饰细胞表面和信号分子来巩固T - R细胞谱系的稳定性，从而适应诱导和维持T - R细胞所需的信号。这种适应包括依赖于Foxp3对环核苷酸磷酸二酯酶3B的抑制，影响负责T - R细胞内稳态的基因。
Regulatory CD4(+) T cells (T-R cells), the development of which is critically dependent on X-linked transcription factor Foxp3 ( forkhead box P3), prevent self-destructive immune responses(1). Despite its important role, molecular and functional features conferred by Foxp3 to T-R precursor cells remain unknown. It has been suggested that Foxp3 expression is required for both survival of T-R precursors as well as their inability to produce interleukin (IL)-2 and independently proliferate after T-cell-receptor engagement, raising the possibility that such 'anergy' and T-R suppressive capacity are intimately linked(2-4). Here we show, by dissociating Foxp3-dependent features from those induced by the signals preceding and promoting its expression in mice, that the latter signals include several functional and transcriptional hallmarks of T-R cells. Although its function is required for T-R cell suppressor activity, Foxp3 to a large extent amplifies and fixes pre-established molecular features of T-R cells, including anergy and dependence on paracrine IL-2. Furthermore, Foxp3 solidifies T-R cell lineage stability through modification of cell surface and signalling molecules, resulting in adaptation to the signals required to induce and maintain T-R cells. This adaptation includes Foxp3-dependent repression of cyclic nucleotide phosphodiesterase 3B, affecting genes responsible for T-R cell homeostasis.