A common hematopoietic precursor to innate lymphoid cells

先天性淋巴细胞（inate lymphocyte，ILC）是一类位于粘膜屏障上的淋巴细胞， 在清除感染、诱导过敏性炎症或指导组织修复中起作用。不同血统的 ILC专门分泌极化的细胞因子，这些细胞因子协调快速的保护性反应 对抗各种病原体因此，他们的研究与广泛的疾病有关， 西方和第三世界国家。 ILC2、ILC22、ILC23、ILC24、ILC26、ILC28、ILC29、IL 淋巴组织诱导物（LTis）和NK细胞，了解甚少，存在相当大的混乱 关于这些ILC在健康状态和疾病情况下的身份和功能。在 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， 仅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 也适用于正常动物。 本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 显示转录因子PLZF，以前被鉴定为先天性NKT细胞的标志， 在ILC 2和ILC 22的发育过程中也以高水平表达，但在NK或LTi细胞的发育过程中不表达。 中心假设是PLZF标志着ILC 2和ILC 22的共同骨髓前体， 对正常发育和功能至关重要。本申请的目的是使用PLZF-IRES-GFPCre 小鼠来鉴定ILC的骨髓前体，表征它们的分子特征和遗传学特征。 在体内操作ILC，以确定它们在良好建立的肠道感染模型中的功能。的 具体目的是1）鉴定ILC谱系的PLZF表达骨髓前体，2）表征 其分子特征; 3）创建ILC缺陷小鼠模型用于肠道感染的研究。该提案 是创新的和重要的，因为它鉴定了一种新的骨髓前体和一种新的转录， 因为它将产生在感染背景下研究ILC的模型， 免疫活性动物。

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 specific 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.