Bone Morphogenic Protein Receptor 1a signaling controls stability of Treg cell phenotype

骨形态发生蛋白受体 1a 信号传导控制 Treg 细胞表型的稳定性

基本信息

批准号：
10727297
负责人：
Piotr J. Kraj
金额：
$ 24.8万
依托单位：
OLD DOMINION UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-21 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727297
关键词：
ATAC-seq Adhesions Agonist Antigens Apoptosis Autoimmune Autoimmune Diseases Autoimmunity BMP2 gene Biological Process Bone Morphogenetic Proteins CD4 Positive T Lymphocytes Cell Aging Cell Cycle Cell Separation Cell physiology Cell secretion Cells Chromatin Structure Collaborations Complex Cues Data Development Disease Down-Regulation Effector Cell Epigenetic Process Equilibrium FOXP3 gene Family Gene Expression Gene Expression Profiling Generations Genetic Transcription HIF1A gene Homeostasis IL17 gene Immune Immunologics In Situ Individual Inflammation Inflammatory Interferon Type II Maintenance Modification Molecular Mus Pathology Patients Peptides Peripheral Phenotype Play Polycomb Reaction Regulatory T-Lymphocyte Reporting Research Rheumatoid Arthritis Role Signal Pathway Signal Transduction Signaling Protein T-Lymphocyte Subsets TNF gene Testing Therapeutic Thymus Gland Tissues Transcriptional Regulation Transforming Growth Factor beta Transforming Growth Factor beta Receptors Up-Regulation activin A antagonist bone morphogenetic protein receptors cell motility cell type clinically significant cytokine design epigenetic regulation epigenome immunoregulation in vivo inflammatory milieu inhibitor insight member mouse model novel therapeutic intervention overexpression peptidomimetics peripheral tolerance pharmacologic preservation prevent programs receptor response senescence transcription factor transcriptome transcriptome sequencing

项目摘要

Abstract Despite extensive studies, environmental cues and signaling circuits regulating onset of autoimmune diseases are not completely understood. Here we report that a receptor of the TGF-β cytokine family, Bone Morphogenetic Protein Receptor 1α (BMPR1α, Alk-3) has important immunoregulatory functions. BMPR1α is upregulated by activated effector and Foxp3+ regulatory CD4+ T cells (TR cells) and modulates functions of both of these cell types. BMPR1α regulates inflammation by inhibiting generation of Th17 cells and sustaining TR cells. Abrogation of BMPR1α signaling in TR cells resulted in a gradual loss of Foxp3 expression and upregulation of transcription factors and cytokines specific for Th effector lineage including Rorgt, Batf, Hif1a, IL-17 and IFN-g. This data suggests that BMPR1α controls phenotypic stability of TR cells and regulates Th17/TR balance, critical for maintenance of peripheral tolerance and protection from autoimmune diseases. Cells which downregulate Foxp3 convert into effector Th cells (exTR cells) which produce proinflammatory cytokines and contribute to disease pathology in a number of autoimmune diseases. A recent RNA-seq transcriptome analyses of BMPR1α-deficient TR cells in situ showed upregulation of a number of epigenetic modifiers and transcription factors specific for effector Th cells including Med14, Supt16H, Setbp1, Tbx21 (Tbet) and Maf. These new data demonstrate that BMPR1α-deficient TR cells in unmanipulated mice are predisposed to follow epigenetic and transcription programme to dedifferentiate to exTR cells when subject to antigenic stimulation and inflammation. To gain mechanistic insight on the immunoregulatory role of BMPR1α we will combine ATAC-seq and RNA- seq analyses of epigenetic profile and transcriptomes to identify molecules involved in TR/exTR transition. We will test if TR/exTR transition can be regulated by pharmacological modulation of BMPR1α dependent signaling pathways. We have found that at the molecular level BMPR1a deficiency in TR cells led to upregulation of Kdm6b (Jmjd3) demethylase, an antagonist of polycomb repressive complex 2 (PRC2). We will examine if phenotype of BMPR1a deficient TR cells could be sustained by Kdm6b inhibitor. We will also generate mouse models to test additional compounds for their ability to impact BMPR1a signaling and modulate TR cell stability. In summary, proposed research will contribute to our understanding of immunoregulation and has the potential to outline new therapeutic strategies for inflammatory and autoimmune diseases.

抽象的尽管进行了大量研究，环境线索和信号通路调节自身免疫性疾病的发作疾病尚未完全了解，在此我们报道了 TGF-β 细胞因子家族的受体——骨。形态发生蛋白受体 1α (BMPR1α, Alk-3) 具有重要的免疫调节功能。被激活的效应子和 Foxp3+ 调节性 CD4+ T 细胞（TR 细胞）上调，并调节这两种细胞类型都通过抑制 Th17 细胞的生成和维持来调节炎症。 TR 细胞中 BMPR1α 信号传导的废除导致 Foxp3 表达逐渐丧失，并且上调 Th 效应谱系特异的转录因子和细胞因子，包括 Rorgt、Batf、Hif1a、 IL-17 和 IFN-g 该数据表明 BMPR1α 控制 TR 细胞的表型稳定性并调节。 Th17/TR 平衡对于维持外周耐受性和预防自身免疫性疾病至关重要。下调 Foxp3 的细胞转化为产生促炎性的效应 Th 细胞（exTR 细胞）细胞因子并有助于许多自身免疫性疾病的疾病病理学。原位 BMPR1α 缺陷 TR 细胞的转录组分析显示许多表观遗传上调效应 Th 细胞特异的修饰因子和转录因子，包括 Med14、Supt16H、Setbp1、Tbx21 （Tbet）和马夫。这些新数据表明，未经操作的小鼠中 BMPR1α 缺陷的 TR 细胞倾向于当受到抗原影响时，遵循表观遗传和转录程序去分化为 exTR 细胞刺激和炎症。为了深入了解 BMPR1α 的免疫调节作用，我们将结合 ATAC-seq 和 RNA- 对表观遗传图谱和转录组进行 seq 分析，以识别参与 TR/exTR 转换的分子。我们将测试 TR/exTR 转换是否可以通过 BMPR1α 依赖的药理学调节来调节我们发现TR细胞中BMPR1a缺陷在分子水平上导致。 Kdm6b (Jmjd3) 去甲基酶（多梳抑制复合物 2 (PRC2) 的拮抗剂）的上调。检查 BMPR1a 缺陷 TR 细胞的表型是否可以通过 Kdm6b 抑制剂维持。生成小鼠模型来测试其他化合物影响 BMPR1a 信号传导的能力总之，所提出的研究将有助于我们对 TR 细胞稳定性的理解。免疫调节，并有可能概述炎症和自身免疫的新治疗策略疾病。