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

• 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
• 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

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.

摘要 尽管进行了广泛的研究，但环境因素和调节自身免疫性疾病发病的信号通路仍然存在。 疾病并不完全清楚。在这里，我们报告说，TGF-β细胞因子家族的受体，骨 形态发生蛋白受体1α（MorphogeneticProteinReceptor 1α，BMPR 1 α，Alk-3）具有重要的免疫调节功能。BMPR 1 α是 由活化的效应细胞和Foxp 3+调节性CD 4 + T细胞（TR细胞）上调，并调节 这两种细胞类型。BMPR 1 α通过抑制Th 17细胞的生成和维持 TR细胞。TR细胞中BMPR 1 α信号的消除导致Foxp 3表达的逐渐丧失， 上调对Th效应子谱系特异的转录因子和细胞因子，包括Rogt，Batf，Hif 1a， IL-17和IFN-g。这些数据表明，BMPR 1 α控制TR细胞的表型稳定性，并调节TR细胞的表型稳定性。 Th 17/TR平衡，对于维持外周耐受性和保护免受自身免疫性疾病至关重要。 下调Foxp 3的细胞转化为效应Th细胞（exTR细胞），其产生促炎性细胞因子， 细胞因子，并有助于在许多自身免疫性疾病的疾病病理。最近的RNA-seq 原位BMPR 1 α缺陷TR细胞的转录组分析显示， 效应Th细胞特异性的修饰物和转录因子，包括Med 14、Supt 16 H、Setbp 1、Tbx 21 （Tbet）和Maf. 这些新的数据表明，在未经操作的小鼠中，BMPR 1 α缺陷的TR细胞倾向于 遵循表观遗传和转录程序，以在受到抗原诱导时去分化为exTR细胞。 刺激和炎症。 为了深入了解BMPR 1 α的免疫调节作用，我们将联合收割机ATAC-seq和RNA- 表观遗传谱和转录组的seq分析，以鉴定参与TR/exTR转换的分子。 我们将测试TR/exTR转换是否可以通过药理学调节BMPR 1 α依赖性 信号通路我们已经发现，在分子水平上，TR细胞中BMPR 1a缺陷导致了 Kdm 6 b（Jmjd 3）去甲基化酶的上调，其是多梳抑制复合物2（PRC 2）的拮抗剂。我们将 检测Kdm 6 b抑制剂是否能维持BMPR 1a缺陷型TR细胞的表型。我们还将 产生小鼠模型以测试另外的化合物影响BMPR 1a信号传导的能力， 调节TR细胞稳定性。总之，拟议的研究将有助于我们了解 免疫调节，并有可能概述新的治疗策略，炎症和自身免疫性 疾病