A common hematopoietic precursor to innate lymphoid cells

描述（由申请人提供）：先天淋巴细胞（ILC）是一种新的淋巴细胞群，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作用。不同谱系的ILCs专门分泌极化的细胞因子，这些细胞因子协调针对各种类型病原体的快速保护反应。因此，他们的研究与西方和第三世界国家的广泛疾病有关。不同群体的ILCs，包括ILC2s、ILC22s、淋巴组织诱导剂（LTis）和NK细胞之间的发育和谱系关系尚不清楚，并且在健康状态和疾病背景下，这些ILCs的身份和功能存在相当大的混乱。由于缺乏允许在体内对这些谱系进行特异性操作的遗传模型，研究主要局限于缺乏适应性免疫系统的免疫缺陷小鼠，目前尚不清楚他们的结论是否适用于正常动物。该项目建立在我们实验室生产的PLZF- ires - gfpcre报告小鼠的初步研究基础上，表明转录因子PLZF，先前被确定为先天性样NKT细胞谱系的特征，在ILC2s和ilc22的发育过程中也高水平表达，但NK或LTi细胞则不表达。核心假设是PLZF标志着ILC2s和ilc22的共同骨髓前体，并且对正常发育和功能至关重要。本应用程序的目的是使用PLZF-IRES-GFPCre小鼠鉴定ILCs的骨髓前体，表征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。具体目的是1)鉴定ILC谱系中表达plzf的骨髓前体，2)表征其分子特征；3)建立ilc缺陷小鼠模型用于肠道感染研究。该建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ILCs的新转录因子，并且因为它将为免疫功能正常的动物感染背景下的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.