Bone Morphogenic Protein signaling in Th/Treg lineage specification

摘要 转化生长因子-β(转化生长因子-β)家族细胞因子调节细胞分化和形态发生，细胞 增殖和迁移、上皮向间充质转化和转移性扩散。转化生长因子β是一种 免疫调节细胞因子抑制CD4效应细胞的激活和分化并促进 Foxp3调节性T细胞的抑制功能。尽管人们对转化生长因子-β如何调节T细胞有更多的了解 细胞功能，转化生长因子-β细胞因子家族中许多其他成员的免疫调节作用，特别是 骨形态发生蛋白(BMPs)在很大程度上仍不清楚。 我们已经发现，骨形态发生蛋白受体1α(BMPR1α，ALK-3)由NAIVE和ALK-3表达。 活化的CD4T细胞和Foxp3调节性T(Tr)细胞，调节功能效应器Th和tr细胞。 阻断α信号导致高表达促炎性Th1/Th17效应细胞的产生 炎性细胞因子、干扰素-γ、白介素17和肿瘤坏死因子家族蛋白的水平。BMPR1α缺陷的CD4T细胞不 生成自适应TR(ATR)信元。外周TR细胞BMPR1Foxp3基因失活降低α表达 导致tr表型的不稳定和extr细胞的积累。JMJD3(KDM6B)去甲基酶 在TR细胞中被确定为BMPR1α信号的靶标和表观遗传学变化作为丢失抑制物的原因 功能。我们推测BMP和BMPR1α可能代表了形成表观遗传学的调控模块 转化生长因子-β介导转录调控的景观和启动T细胞。 BMPR1α不是唯一与BMP结合的受体，这些细胞因子还可能结合包括ALK2在内的激活素受体。 为了进一步从机制上了解BMPs和转化生长因子-β如何调节外周血Th和tr细胞的功能，我们 建议建立Alk2基因在所有T细胞或TR细胞中缺失的条件性基因敲除小鼠。Alk2突变体 小鼠将与在各自T细胞亚群中缺乏BMPR1α基因的小鼠进行比较。这项提案的目标是 是生产实验小鼠，可以对其进行检查，以了解alk2和bmpr1α如何合作 传递骨形态发生蛋白和转化生长因子-β介导的信号调节CD4Th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.