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Human intestinal innate lymphoid cells (ILCs): signatures and polarization signals

人肠道先天淋巴细胞 (ILC)：特征和极化信号

基本信息

批准号：
289483678
负责人：
Professorin Dr. Chiara Romagnani, Ph.D.
金额：
--
依托单位：
Institut für Medizinische Immunologie (CVK)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/289483678?language=en
关键词：
Human intestinal innate lymphoid cells

项目摘要

The immune system responds to pathogen infection by employing distinct effector modules, namely type 1 (Interferon-gamma and Tumor necrosis factor), type 2 (Interleukin-, IL-4, IL-5 and IL-13) and type 3 or 17 (IL-17, IL-22), which are tailored to eliminate the different infectious agents and differentially contribute to drive chronic inflammation, especially inflammatory bowel diseases (IBD). This heterogeneity of effector programs has been extensively characterized among CD4+ T helper (Th) cells which can be accordingly dissected in three main subsets, namely Th1, Th2 and Th17 cells. It is now evident that an emerging family of innate lymphoid cells (ILCs, comprising of Natural Killer cells, ILC1, ILC2 and ILC3), exhibit an analogous heterogeneity of effector programs as described for T cells. Thus, it was shown that different ILC subsets, preferentially residing in the intestine, can play an important role in inducing colitis. On the other hand, ILCs can also contribute to mucosal tissue homeostasis and intestinal epithelial cell regeneration after damage. The signals responsible for the differentiation toward different ILC subset fate and for the imprinting of the correspondent effector programs remain largely unclear, especially in humans.This project is devoted to study the signals required for the differentiation and imprinting of inflammatory and regulatory programs employed by distinct human ILC subsets and to establish protocols for their generation and expansion. We postulate that the intestine might represent a preferential differentiation site for ILCs, especially ILC3, and that gut microenvironment might provide important signals to skew ILC fate. The comparative analysis of human intestinal ILCs and of their precursors with those generated in vitro upon exposure to different stimuli will enable us to get insights on how, where and when distinct effector programs are acquired by ILCs. Because of their crucial role as regulators of inflammatory processes and tissue homeostasis, this project will enable not only to extend our understanding of ILC biology, but also to possibly identify novel therapeutic strategies for the treatment of inflammatory diseases.

免疫系统通过使用不同的效应模块来响应病原体的感染，即1型(干扰素和肿瘤坏死因子)，2型(白介素4、白介素5和白介素13)和3型或17型(白介素17、白介素22)，这些模块是为消除不同的感染源而定制的，对推动慢性炎症，特别是炎症性肠病(IBD)有不同的贡献。这种效应程序的异质性在CD4+T辅助细胞(Th)中得到了广泛的表征，因此可以将其分解为三个主要亚群，即Th1、Th2和Th17细胞。现在很明显，一个新兴的天然淋巴样细胞(ILCs)家族，包括自然杀伤细胞、ILC1、ILC2和ILC3，表现出类似于T细胞所描述的效应程序的异质性。因此，不同的ILC亚群优先存在于肠道中，在结肠炎的发生中起重要作用。另一方面，ILCs还可以促进损伤后粘膜组织的动态平衡和肠上皮细胞的再生。负责分化为不同ILC亚集命运和相应效应程序印记的信号仍然很不清楚，特别是在人类中。本项目致力于研究不同人类ILC亚集所使用的炎性和调节程序的分化和印记所需的信号，并建立它们的产生和扩展的方案。我们推测，肠道可能是ILC，特别是ILC3的优先分化部位，肠道微环境可能为扭曲ILC的命运提供了重要信号。对人类肠道ILC及其前体细胞与体外产生的ILC在不同刺激下的比较分析将使我们能够深入了解ILC如何、何时、何地获得不同的效应程序。由于它们在炎症过程和组织内稳态中起着重要的调节作用，这个项目不仅能够扩大我们对ILC生物学的理解，而且可能找到治疗炎症性疾病的新的治疗策略。