BCL11B in Immune Regulation

描述（由申请人提供）：调节性T（Treg）细胞是外周耐受的主要介质，其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（天然（n）Treg细胞）或在特定条件下由外周中的常规CD 4 + T细胞形成（适应性或诱导（i）Treg细胞）。转录因子Foxp 3对Treg细胞的发育和功能至关重要，Foxp 3基因座的突变会导致人类和小鼠中与致命炎症相关的淋巴组织增生性疾病。nTreg和iTreg细胞中的Foxp 3表达由Foxp 3基因座处的几个保守非编码序列（CNS）控制。解读Treg细胞中Foxp 3的表达如何调节和维持，哪些转录因子调节其表达以及它们如何调节Foxp 3基因座的染色质，对于理解Treg细胞稳定性和自身免疫保护至关重要。我们的初步结果表明，在转录因子Bcl 11b的情况下产生的Treg细胞表达Foxp 3水平降低，促炎细胞因子增加，抑制功能降低，并且具有Bcl 11b-/- Treg细胞的小鼠发展为炎症性肠病（IBD）。此外，在不存在Bcl 11b的情况下，Foxp 3的诱导和从常规CD 4 + T细胞产生iTreg细胞减少。我们发现，Bcl 11b结合Foxp 3启动子，以及CNS 1和CNS 2。在这里，我们提出的研究破译的机制，Bcl 11 b控制Foxp 3在Treg群体的表达，以及如何影响Treg细胞的稳定性。所提出的研究在高度相关的领域具有重大意义，即Treg稳定性和Foxp 3表达的表观遗传控制，并且还与自身免疫性疾病，特别是IBD具有高度相关性。

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.