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

免疫系统通过采用不同的效应器模块，即1型，对病原体感染作出反应。在一些实施方案中，炎症因子包括2型（干扰素-γ和肿瘤坏死因子）、2型（白细胞介素-、IL-4、IL-5和IL-13）和3型或17型（IL-17、IL-22），它们被定制以消除不同的感染因子并差异性地促进慢性炎症，特别是炎性肠病（IBD）。效应程序的这种异质性在CD 4 + T辅助（Th）细胞中得到了广泛的表征，因此可以将其分为三个主要亚群，即Th 1、Th 2和Th 17细胞。现在很明显，一个新兴的先天淋巴样细胞家族（ILC，包括自然杀伤细胞、ILC 1、ILC 2和ILC 3）表现出与针对T细胞所述的效应程序类似的异质性。因此，显示了不同的ILC亚群，优先驻留在肠中，可以在诱导结肠炎中发挥重要作用。另一方面，ILC还可以促进粘膜组织的稳态和损伤后的肠上皮细胞再生。负责向不同的ILC亚群的命运分化和相应的效应程序的印记的信号仍然很大程度上不清楚，特别是在human.This项目致力于研究所需的信号的分化和印记的炎症和调节程序所采用的不同的人类ILC亚群，并建立其生成和扩增的协议。我们推测肠道可能是ILC，特别是ILC 3的优先分化位点，肠道微环境可能提供了重要的信号，以倾斜ILC的命运。人类肠道ILC及其前体与体外暴露于不同刺激后产生的ILC的比较分析将使我们能够深入了解ILC如何，在何处以及何时获得不同的效应程序。由于它们作为炎症过程和组织稳态调节剂的关键作用，该项目不仅能够扩展我们对ILC生物学的理解，而且还可能确定治疗炎症性疾病的新治疗策略。

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.