Mechanisms Controlling Regulatory T cell Effector Function in IBD

IBD 中调节性 T 细胞效应功能的控制机制

基本信息

批准号：
10001469
负责人：
ROBIN D HATTON
金额：
$ 52.95万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-19 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10001469
关键词：
Ablation Antigens CD4 Positive T Lymphocytes Cells Chronic Colitis Crohn&apos s disease Cytokine Signaling DNA Binding Data Development FOXP3 gene GFI1 gene Gene Expression Genes Genetic Transcription Genetic study Homeostasis Human Human Genetics IL10 gene IL10RB gene Immune Immune System Diseases Immunity Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-10 Interleukin-2 Interleukin-6 Intervention Intestinal Diseases Intestines Lamina Propria Large Intestine Longitudinal Studies Lymphoid Tissue Maintenance Mediating Modeling Molecular Mus Mutation Myeloid Cells Pathogenesis Pathogenicity Patients Phenotype Play Production Regulatory T-Lymphocyte Reporter Repression Role Signal Transduction Source T-Lymphocyte T-Lymphocyte Subsets Testing Th1 Cells Therapeutic Trans-Activators Transgenic Organisms cell type cytokine early onset effector T cell gut microbiota immunoregulation inflammatory disease of the intestine inflammatory milieu interleukin-10 receptor intestinal homeostasis microbiota mouse model novel strategies novel therapeutic intervention prevent response transcription factor transcriptome

项目摘要

PROJECT SUMMARY Mechanisms Controlling Regulatory T Cell Effector Function in IBD. The pathogenesis of inflammatory bowel disease (IBD) is characterized by immune dysregulation to components of the enteric microbiota. Findings from mouse models of IBD and recent human genetic studies highlight a critical, non-redundant role for the immunoregulatory cytokine IL-10 in the maintenance of intestinal immune homeostasis. Our lab has shown that Foxp3+ regulatory T (Treg) cells are, overwhelmingly, the major source of IL-10 in the intestines. However, IL-10 is only produced by a subset of Treg cells—defined as ‘effector’ (e)Treg cells. In preliminary studies that used an IL-10 transgenic reporter mouse model to explore differences between transcriptomes of T cells separated on the basis of expression of IL-10, we identified the DNA-binding factor Gfi1 as a central repressor of Il10 gene expression in all subsets of CD4 T cells, including Treg cells. Gfi1 appears to act both directly, via interactions with the Il10 locus, and indirectly, by repressing transcription of Prdm1 (Blimp1), which is a trans-activator of Il10 in Treg cells. Additionally, Gfi1 represses other genes that appear to be central to eTreg function, suggesting that Gfi1 may play a key role in regulating the differentiation of eTreg cells. Finally, we have identified cytokine signals that induce the expression of IL-10 by Foxp3+ Treg cells. In essence, IL-10 expression by Treg cells is Iatent and requires activating cytokine signals that repress Gfi1 to derepress transcription of Il10 as part of eTreg cell programming. This could explain why IL-10 expression by T cells is largely restricted to the intestines at homeostasis, where on-going responses to the microbiota provide a state of controlled inflammation and a source of pro-inflammatory cytokines that promote the development of IL-10– expressing eTreg cells. We hypothesize that inflammatory signals in the gut override Gfi1-mediated repression of eTreg cell development and that modulation of Gfi1 expression will impact the protective capabilities of Treg cells in an inflammatory environment—in large part through modulation of IL-10 expression. Further, we posit that Gfi1 maintains a pathogenic phenotype in CD4 T effector cells by repressing IL-10, such that inhibition of Gfi1 will convert pathogenic T cells to IL-10–producing protective T cells, thereby ameliorating intestinal disease. Herein, we will define mechanisms by which Gfi1 represses IL-10 in murine and human Treg cells and we will perform proof-of-principle studies to examine the impact on IBD pathogenesis of dysregulated expression of Gfi1 by T cells. The delineation of mechanisms by which cytokines modulate the Gfi1–Blimp1 axis to control IL-10 expression by T cells will lead to a better understanding of homeostatic networks that prevent IBD, and will provide a basis for discovery of novel therapeutic approaches by which endogenous IL- 10 can be up-regulated, and the differentiation and function of eTreg cells enhanced, to treat IBD.

项目摘要控制IBD中调节T细胞效应函数的机制。炎症性肠的发病机理疾病（IBD）的特征是免疫失调对促进菌群的成分。鼠标的发现 IBD和最近的人类遗传研究模型突出了免疫调节的关键，非冗余的作用维持肠道免疫稳态的细胞因子IL-10。我们的实验室表明foxp3+调节t （TREG）绝大多数是肠中IL-10的主要来源。但是，IL-10仅产生由Treg细胞的子集（被定义为“效应子”（E）Treg细胞。在使用IL-10的初步研究中转基因报告基因小鼠模型，以探索在分离的T细胞转录组之间的差异 IL-10表达的基础，我们将DNA结合因子GFI1鉴定为IL10基因的中央复制品在包括Treg细胞在内的CD4 T细胞的所有子集中的表达。 GFI1似乎通过交互直接起作用与IL10基因座，并间接地通过表达PRDM1（Blimp1）的转录，这是 Treg细胞中的IL10。另外，GFI1副本似乎是ETREG函数核心的其他基因表明GFI1可能在调节ETREG细胞的分化中起关键作用。最后，我们有鉴定出影响FOXP3+ Treg细胞IL-10表达的细胞因子信号。本质上，IL-10 Treg细胞的表达是有益的，需要激活抑制GFI1的细胞因子信号 IL10作为ETREG细胞编程的一部分的转录。这可以解释为什么T细胞的IL-10表达是在体内稳态上的肠道很大程度上仅限受控注射和促炎细胞因子的来源，促进IL-10 –的发展表达ETREG细胞。我们假设肠道覆盖GFI1介导的表示中的炎症信号 ETREG细胞发育以及GFI1表达的调节将影响Treg的受保护能力在炎症环境中的细胞 - 很大程度上是通过调节IL-10表达。此外，我们定位 GFI1通过反映IL-10来维持CD4 T效应细胞中的致病表型，以便抑制 GFI1将将致病性T细胞转换为IL-10的受保护的T细胞，从而改善肠道疾病。在此，我们将定义机制，鼠和人treg细胞中的GFI1副本IL-10以及我们将执行原则研究证明，以检查对失调的IBD发病机理的影响 T细胞的GFI1表达。细胞因子调节GFI1 – Blimp1的机制的描述通过T细胞控制IL-10表达的轴将使人们更好地理解稳态网络防止IBD，并将为发现新型治疗方法提供基础 10可以上调，并且ETREG细胞的分化和功能增强以治疗IBD。