成骨蛋白BMP调控转录因子Id2的分子机制及其在先天淋巴细胞分化中的作用

Innate lymphoid cells (ILCs) are an emerging family of innate effector cells that react promptly to a wide array of signals and serve important roles in inflammation, immunity against infectious microorganisms as well as lymphoid tissue formation, tissue repair and homeostasis. There are many similarities between ILCs and effector T cells in terms of their functions, diversities and the requirement for specific transcription factors during their differentiation; therefore, ILCs are considered the innate counterparts of effector T cells. All ILCs are derived from BM progenitor cells, however, the extracellular signals and the intracellular transcription factor network that regulates the differentiation of ILCs remain elusive. Our previous study discovered that BM progenitor cells express receptor for bone morphogenic proteins (BMPs) which are involved in the differentiation of many cell types. Using in vitro co-culture system and Id2 reporter mouse model we aim to investigate the mechanism by which BMP signal regulates the expression of Id2 in the ILC progenitors and the role of BMP in the development of ILCs from BM progenitors. Studying the differentiation process of ILC will allow us to understand the requirement for ILC generation as well as their functions, and to develop therapeutics with ILCs in the future.

先天淋巴细胞是近年来新发现的一个免疫细胞家族，在免疫防御、炎症反应和淋巴组织形成及修复过程中都发挥重要作用。它们在细胞类群、功能和发育所必须的转录因子等方面都与效应T细胞有诸多相似性，也因此被视为效应T细胞在固有免疫里的对等效应细胞。ILC的发育起源于骨髓前驱细胞，这个过程受到不同的微环境因子和转录因子的协同作用，然而我们对于这些关键因子的认识尚且十分缺乏。我们的前期研究发现ILC前驱细胞表达成骨蛋白BMP的受体，BMP在多种细胞的发育和分化中起到重要作用。本项目将利用体外细胞共培养模型及决定ILC发育的关键转录因子Id2报告基因小鼠模型探究BMP对Id2的调控及其机制；阐明BMP在ILC定向分化及细胞功能中的作用。研究BMP在ILC的发育分化过程中的表达及其效应有助于我们了解ILC形成所需的条件，也为开发促进或抑制ILC分化的药物靶标和治疗ILC相关疾病提供新理论依据。

先天淋巴细胞是近年来新发现的一个免疫细胞家族，在免疫防御、炎症反应和淋巴组织形成及修复过程中都发挥重要作用。它们在细胞类群、功能和发育所必须的转录因子等方面都与效应T细胞有诸多相似性，也因此被视为效应T细胞在固有免疫里的对等效应细胞。ILC的发育起源于骨髓前驱细胞，这个过程受到不同的微环境因子和转录因子的协同作用，然而我们对于这些关键因子的认识尚且十分缺乏。我们的前期研究发现ILC前驱细胞表达成骨蛋白受体BMPR2，BMP在多种细胞的发育和分化中起到重要作用。本项目利用体外细胞共培养系统、BMP转基因小鼠模型和BMPR2条件性敲除小鼠模型探究了BMP/BMPR2信号通路在ILC发育分化过程中的作用，发现BMP可促进ILC2的生成，BMP信号的缺失导致外周粘膜组织ILC2的减少，而骨髓中淋巴祖细胞及骨髓ILC2的增加，揭示了BMP/BMPR2信号对ILC2亚群的特异性调控作用。研究BMP在ILC的发育分化过程中的表达及其效应有助于我们了解ILC形成所需的条件，也为开发促进或抑制ILC分化的药物靶标和治疗ILC相关疾病提供新理论依据。