A mechanism for expansion of regulatory T-cell repertoire and its role in self-tolerance.
A mechanism for expansion of regulatory T-cell repertoire and its role in self-tolerance.
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DOI：
10.1038/nature16141
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发表时间：
2015-12-03
期刊：
影响因子：
64.8
通讯作者：
Rudensky AY
中科院分区：
文献类型：
--
作者：
Feng Y;van der Veeken J;Shugay M;Putintseva EV;Osmanbeyoglu HU;Dikiy S;Hoyos BE;Moltedo B;Hemmers S;Treuting P;Leslie CS;Chudakov DM;Rudensky AY
T细胞受体(TCR)信号在决定T细胞命运中起着关键作用。在一定的低亲和力范围内表达TCR的前体细胞对自身多肽-MHC复合体进行正向选择，并分化为表达高度多样化的自身MHC限制性TCR谱系的幼稚T细胞。相反，显示与“自我”具有高亲和力的TCR的前体要么通过TCR激动剂诱导的凋亡(负选择)被消除，要么被调节性的CD4+T(Treg)细胞抑制，其分化和功能由X染色体编码的转录因子Foxp3控制(综述)。Foxp3在一小部分自身反应性T细胞中表达，这些T细胞在激动剂驱动的TCR信号和白细胞介素2(IL-2)受体信号相结合的反应中逃脱了阴性选择。除了Treg细胞，TCR激动剂驱动的选择还会产生其他几种特殊的T细胞系，如NKT和MAIT细胞。尽管后者表现出有限的TCR谱系，但Treg细胞表现出高度多样化的TCR集合，在这里，我们探索了一种特殊的机制是否能够使激动剂驱动的Treg细胞选择具有不同TCR谱系的Treg细胞及其对自我耐受的意义。我们发现，内含子Foxp3增强子CNS3作为表观遗传开关，赋予前体细胞中Foxp3启动子一种稳定的状态，使Treg细胞对广泛的TCR刺激，特别是次优刺激做出反应。依赖于CNS3的TCR谱系的扩增使Treg细胞能够有效地控制自我反应性T细胞，特别是当胸腺负选择受到遗传损害时。我们的发现强调了这两种主要的自我容忍机制的互补作用。
T cell receptor (TCR) signaling plays a key role in T cell fate determination. Precursor cells expressing TCRs within a certain low affinity range for self peptide-MHC complexes undergo positive selection and differentiate into naïve T cells expressing a highly diverse self-MHC restricted TCR repertoire. In contrast, precursors displaying TCRs with a high affinity for “self” are either eliminated through TCR agonist induced apoptosis (negative selection) or restrained by regulatory CD4+ T (Treg) cells, whose differentiation and function are controlled by the X-chromosome encoded transcription factor Foxp3 (review). Foxp3 is expressed in a fraction of self-reactive T cells that escape negative selection in response to agonist driven TCR signals combined with interleukin-2 (IL-2) receptor signaling. In addition to Treg cells, TCR agonist-driven selection results in the generation of several other specialized T cell lineages like NKT and MAIT cells. Although the latter exhibit a restricted TCR repertoire, Treg cells display a highly diverse collection of TCRs, Here we explored whether a specialized mechanism enables agonist driven selection of Treg cells with a diverse TCR repertoire and its significance for self-tolerance. We found that intronic Foxp3 enhancer CNS3 acts as an epigenetic switch that confers a poised state to the Foxp3 promoter in precursor cells to make Treg cell lineage commitment responsive to a broad range of TCR stimuli, particularly to suboptimal ones. CNS3-dependent expansion of the TCR repertoire enables Treg cells to effectively control self-reactive T cells, especially when thymic negative selection was genetically impaired. Our findings highlight the complementary roles of these two main mechanisms of self-tolerance.