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

摘要 尽管进行了广泛的研究，但环境线索和信号回路调节自身免疫的启动 人们对疾病的了解还不完全。在此，我们报道了转化生长因子-β细胞因子家族的一种受体，骨 形态发生蛋白受体1α(α，ALK-3)具有重要的免疫调节功能。BMPR1α为 由激活的效应器和Foxp3+调节性CD4+T细胞(TR细胞)上调，并调节 这两种细胞类型。BMPR1α通过抑制Th17细胞的产生和维持而调节炎症 Tr细胞。在TR细胞中BMPR1α信号的缺失导致Foxp3表达的逐渐丧失和 上调Th效应细胞系特异的转录因子和细胞因子，包括Rorgt，BATF，HIF1a， IL-17和干扰素-g。这一数据表明，bmpr1α控制着tr细胞的表型稳定性，并调节 Th17/TR平衡，对于维持外周耐受和保护自身免疫性疾病至关重要。 下调Foxp3的细胞转化为产生促炎作用的效应Th细胞(extr细胞) 细胞因子，并在一些自身免疫性疾病的疾病病理中起作用。最近的一次RNA-Seq 原位转录组分析显示BMPR1α缺陷型TR细胞中许多表观遗传学基因上调 效应性Th细胞特异性修饰物和转录因子包括Med14、Supt16H、Setbp1、Tbx21 (Tbet)和Maf. 这些新数据表明，在未经处理的小鼠中，BMPR1α缺陷的TR细胞容易患上 遵循表观遗传和转录程序，当受到抗原影响时，去分化为extR细胞 刺激和发炎。 为了从机制上深入了解bmpr1α的免疫调节作用，我们将atac-seq和rna- 表观遗传学图谱和转录本的SEQ分析，以确定参与tr/extr转换的分子。 我们将测试是否可以通过药物调节依赖于α的BMPR1来调节TR/ExtR的转换 信号通路。我们已经发现，在分子水平上，TR细胞中BMPR1A缺陷导致 多梳抑制复合体2(PRC2)的拮抗剂KDM6B(Jmjd3)去甲基酶上调。我们会 检测KDM6B抑制剂能否维持BMPR1A缺陷型TR细胞的表型。我们还将 生成小鼠模型以测试其他化合物影响BMPR1A信号转导和 调节tr细胞的稳定性。总而言之，拟议的研究将有助于我们对 免疫调节，有可能勾勒出炎症和自身免疫的新治疗策略 疾病。

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.