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

点击翻译按钮获取中文摘要

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.