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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.

摘要