A common hematopoietic precursor to innate lymphoid cells

描述（由申请人提供）：先天淋巴细胞（ILC）是一种新型淋巴细胞群体，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作用。ILC的不同谱系专门分泌极化的细胞因子组，其协调针对各种类别的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ILC群体（包括ILC 2、ILC 22、淋巴组织诱导物（LT）和NK细胞）之间的发育和谱系关系知之甚少，并且关于这些ILC在健康状态和疾病背景下的身份和功能存在相当大的混淆。在缺乏遗传模型的情况下，允许在体内对这些谱系进行特异性操作，研究主要限于缺乏适应性免疫系统的免疫缺陷小鼠，目前还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的基础上，该研究表明，先前被鉴定为先天样NKT细胞谱系的标志的转录因子PLZF在ILC 2和ILC 22的发育过程中也以高水平表达，但在NK或LTi细胞中则不表达。中心假设是PLZF标志着ILC 2和ILC 22的共同骨髓前体，并且对于正常发育和功能至关重要。本申请的目的是使用PLZF-IRES-GFPCre小鼠鉴定ILC的骨髓前体，表征其分子特征并在体内遗传操作ILC，以确定其在良好建立的肠道感染模型中的功能。具体目的是1）鉴定ILC谱系的表达PLZF的骨髓前体，2）表征其分子特征; 3）建立用于肠道感染研究的ILC缺陷型小鼠模型。该提案是创新的和重要的，因为它确定了一种新的骨髓前体和一种新的ILC转录因子，因为它将产生模型的ILC的研究中的感染免疫活性动物的背景下。

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.