Bone Morphogenic Protein signaling in Th/Treg lineage specification

摘要 转化生长因子-β（TGF-β）家族细胞因子调节细胞分化和形态发生， 增殖和迁移、上皮向间质转化和转移性播散。TGF-β是一种 众所周知，免疫调节细胞因子抑制CD 4+效应细胞活化和分化并促进 Foxp 3+调节性T细胞的抑制功能。尽管对TGF-β如何调节T细胞的理解有所增加， 细胞功能，TGF-β细胞因子家族的许多其他成员的免疫调节作用，特别是 骨形态发生蛋白（BMP）在很大程度上仍是未知的。 我们已经发现，由天然的和非天然的细胞表达的骨形态发生蛋白受体1α（BMPR 1 α，Alk-3）， 活化的CD 4 + T细胞和Foxp 3+调节性T（TR）细胞调节效应Th和TR细胞的功能。 消除BMPR 1 α信号传导导致促炎性Th 1/Th 17效应细胞的产生， 炎症细胞因子、IFN-γ、IL-17和TNF家族蛋白水平。BMPR 1 α缺陷型CD 4 + T细胞不 产生自适应TR（aTR）细胞。外周血TR细胞BMPR 1 α基因失活降低Foxp 3表达 导致TR表型的不稳定和exTR细胞的积累。Jmjd 3（Kdm 6 b）脱甲基酶是 被鉴定为TR细胞中BMPR 1 α信号传导的靶点，表观遗传变化是抑制因子丢失的原因。 功能我们假设BMPs和BMPR 1 α可能代表了影响表观遗传的调控模块， 用于TGF-β介导的转录调节的横向和引发T细胞。 BMPR 1 α不是唯一结合BMP的受体，这些细胞因子也可以结合激活素受体，包括Alk 2。 为了进一步了解BMPs和TGF-β如何调节外周Th和TR细胞的功能， 提出产生条件性敲除小鼠，其中Alk 2基因在所有T细胞或TR细胞中缺失。Alk 2突变体 将小鼠与相应T细胞亚群中缺乏BMPR 1 α基因的小鼠进行比较。这项提案的目的是 是生产实验小鼠，可以检查，以了解Alk 2和BMPR 1 α如何合作， 传递BMP和TGF-β介导的信号以调节CD 4 + Th和TR细胞。

Abstract The transforming growth factor-β (TGF-β) family cytokines regulate cell differentiation and morphogenesis, cell proliferation and migration, epithelial-to-mesenchymal transition and metastatic dissemination. TGF-β is an immunoregulatory cytokine well known to inhibit activation and differentiation of CD4+ effector cells and promote suppressor functions of Foxp3+ regulatory T cells. Despite increased understanding of how TGF-β regulates T cell functions, the immunomodulatory roles of many other members of the TGF-β cytokine family, especially bone morphogenetic proteins (BMPs), remain largely unknown. We have found that Bone Morphogenic Protein Receptor 1α (BMPR1α, Alk-3) expressed by naive and activated CD4+ T cells and Foxp3+ regulatory T (TR) cells, modulates functions effector Th and TR cells. Abrogating BMPR1α signaling leads to generation of pro-inflammatory Th1/Th17 effector cells expressing high levels of inflammatory cytokines, IFN-γ, IL-17 and TNF family proteins. BMPR1α-deficient CD4+ T cells do not generate adaptive TR (aTR) cells. Inactivation of BMPR1α gene in peripheral TR cells reduced Foxp3 expression leading to the instability of TR phenotype and accumulation of exTR cells. Jmjd3 (Kdm6b) demethylase was identified as target of BMPR1α signaling in TR cells and epigenetic changes as a cause of lost suppressor function. We hypothesize that BMPs and BMPR1α may represent regulatory modules shaping epigenetic landscape and priming T cells for transcriptional regulation mediated by TGF-β. BMPR1α is not the only receptor binding BMPs, these cytokines may also bind activin receptors including Alk2. To get further mechanistic insight how BMPs and TGF-β regulate functions of peripheral Th and TR cells we propose to generate conditional knockout mice where Alk2 gene is deleted in all T cells or in TR cells. Alk2 mutant mice will be compared to mice lacking BMPR1α gene in the respective T cell subsets. The goal of this proposal is to produce experimental mice which could be examined to understand how Alk2 and BMPR1α cooperate to deliver BMP and TGF-β mediated signaling to regulate CD4+ Th and TR cells.