BCL11B in Immune Regulation

描述(申请人提供)：调节性T(Treg)细胞是外周耐受的主要媒介，它们的改变是自身免疫性疾病的主要原因之一。Treg细胞在胸腺中发育(自然的(N)Treg细胞)，或在特定条件下(适应性或诱导性的(I)Treg细胞)由外周的常规CD4+T细胞形成。转录因子Foxp3对Treg细胞的发育和功能至关重要，Foxp3基因位点的突变会导致淋巴增殖性疾病，并与致命的炎症相关，在人类和小鼠中都是如此。Foxp3在nTreg和iTreg细胞中的表达受Foxp3基因上几个保守的非编码序列(CNS)控制。破译Foxp3在Treg细胞中的表达是如何调节和维持的，哪些转录因子调节其表达，以及它们如何调节Foxp3基因的染色质，对于理解Treg细胞的稳定性和保护自身免疫是至关重要的问题。我们的初步结果显示，在缺乏转录因子Bcl11b的情况下产生的Treg细胞表达Foxp3水平降低，促炎症细胞因子增加，抑制功能减弱，携带Bcl11b-/-Treg细胞的小鼠发生炎症性肠病(IBD)。此外，在没有Bcl11b的情况下，Foxp3的诱导和从传统的CD4+T细胞产生iTreg细胞的数量减少。我们发现Bcl11b能与Foxp3启动子结合，也能与CNS1和CNS2结合。在这里，我们建议进行研究，以破译Bcl11b控制Treg群体中Foxp3表达的机制，以及这如何影响Treg细胞的稳定性。这些研究在一个高度相关的领域，即Treg的稳定性和Foxp3表达的表观遗传控制方面具有重要意义，也对自身免疫性疾病，特别是IBD具有很高的相关性。

DESCRIPTION (provided by applicant): Regulatory T (Treg) cells are the primary mediators of peripheral tolerance and their alteration is one of the major causes of autoimmune disorders. Treg cells develop in the thymus (natural (n)Treg cells) or are formed from conventional CD4+ T cells in the periphery in specific conditions (adaptive or induced (i)Treg cells). The transcriptio factor Foxp3 is crucial for Treg cell development and function, and mutations at the Foxp3 locus cause lymphoproliferative disorders associated with fatal inflammation, both in humans and mice. Foxp3 expression in nTreg and iTreg cells is controlled by several conserved noncoding sequences (CNS) at the Foxp3 locus. Deciphering how expression of Foxp3 is regulated and maintained in Treg cells, what transcription factors regulate its expression and how they modulate chromatin at Foxp3 locus, are imperative questions critical for understanding Treg cell stability and protection from autoimmunity. Our preliminary results show that Treg cells generated in the absence of the transcription factor Bcl11b express reduced levels of Foxp3, increased proinflammatory cytokines, have reduced suppressive function, and mice with Bcl11b-/- Treg cells develop inflammatory bowel diseases (IBD). Additionally, induction of Foxp3 and generation of iTreg cells from conventional CD4+ T cells are reduced in the absence of Bcl11b. We found that Bcl11b binds Foxp3 promoter, as well as CNS1 and CNS2. Here we propose studies to decipher the mechanisms by which Bcl11b controls expression of Foxp3 in Treg populations, as well as how this influences Treg cell stability. The proposed studies have a major significance in a field of high relevance, namely Treg stability and epigenetic control of Foxp3 expression and also have high relevance for autoimmune diseases, particularly for IBD.