A common hematopoietic precursor to innate lymphoid cells

描述(申请人提供)：天然淋巴细胞(ILC)是一种新型的淋巴细胞群体，存在于粘膜屏障上，在清除感染、诱导过敏性炎症或指导组织修复方面发挥关键功能。不同的ILC谱系专门分泌极化的细胞因子，这些细胞因子可以协调对各种病原体的快速保护性反应。因此，他们的研究与西方和第三世界国家的广泛疾病有关。不同的ILC，包括ILC2s、ILC22s、淋巴组织诱导物(LTIs)和NK细胞之间的发育和谱系关系尚不清楚，在健康状态和疾病背景下这些ILC的身份和功能也存在相当大的混乱。由于缺乏在体内对这些血统进行特定操作的遗传模型，研究在很大程度上仅限于缺乏适应性免疫系统的免疫缺陷小鼠，尚不清楚他们的结论是否适用于正常动物。这个项目建立在对我们实验室生产的PLZF-IRES-GFPCre报告鼠的初步研究基础上，表明转录因子PLZF，以前被认为是先天类NKT细胞谱系的标志，在ILC2s和ILC22s的发育过程中也有高水平的表达，但不表达NK或LTI细胞。中心假设是PLZF标志着ILC2s和ILC22s的共同骨髓前体，对正常发育和功能是必不可少的。本应用的目的是利用PLZF-IRES-GFPCre小鼠鉴定ILCs的骨髓前体细胞，鉴定其分子特征，并在体内对ILCs进行遗传操作，以确定其在已建立的肠道感染模型中的功能。其具体目的是1)鉴定表达PLZF的ILC谱系的骨髓前体，2)鉴定其分子特征，3)建立ILC缺陷小鼠模型，用于肠道感染的研究。这项提议具有创新性和重要意义，因为它确定了一种新的骨髓前体和一种新的ILCs转录因子，还因为它将为免疫活性动物感染背景下的ILCs研究提供模型。

DESCRIPTION (provided by applicant): Innate lymphocytes (ILC) are novel populations of lymphocytes that reside at mucosal barriers and play critical functions in clearing infections, inducing allergic inflammation or directing tissue repair. Different lineages of ILCs are specialized in the secretion of polarized sets of cytokines that orchestrate rapid protective responses against various categories of pathogens. Thus, their study is relevant to a broad range of diseases across western and third-world countries. The development and the lineage relationships between different populations of ILCs, including ILC2s, ILC22s, lymphoid tissue inducers (LTis) and NK cells, are poorly understood and there is considerable confusion regarding the identity and function of these ILCs in the healthy state and in the context of disease. In the absence of genetic models alowing specific manipulation of these lineages in vivo, studies have been largely limited to immunodeficient mice lacking an adaptive immune system and it is unclear whether their conclusions will apply to normal animals. This project builds on preliminary studies of PLZF-IRES-GFPCre reporter mice produced in our laboratory showing that the transcription factor PLZF, previously identified as the signature of the innate-like NKT cell lineage, is also expressed at high levels during the development of ILC2s and ILC22s but not NK or LTi cells. The central hypothesis is that PLZF marks a common bone marrow precursor to ILC2s and ILC22s and is essential for normal development and function. The objective of this application is to use PLZF-IRES-GFPCre mice to identify the bone marrow precursors of ILCs, characterize their molecular signature and genetically manipulate ILCs in vivo in order to define their function in well-established models of enteric infections. The specifc aims are 1) to identify the PLZF-expressing bone marrow precursor of ILC lineages, 2) to characterize its molecular signature; 3) to create ILC-defective mouse models for studies of enteric infections. The proposal is innovative and significant because it identifies a novel bone marrow precursor and a novel transcription factor for ILCs and because it will produce models for studies of ILCs in the context of infections in immunocompetent animals.