A common hematopoietic precursor to innate lymphoid cells

天然淋巴细胞(ILC)是一类新型的淋巴细胞，它们位于粘膜屏障上，发挥着重要的作用 清除感染、引起过敏性炎症或指导组织修复的功能。不同的血统 ILC专门分泌能协调快速保护性反应的极化细胞因子。 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。 ILC2s、ILC22s等不同种群间的发育及血缘关系 淋巴组织诱导物(LTIs)和NK细胞知之甚少，存在相当大的混乱 关于这些ILC在健康状态下和在疾病背景下的身份和功能。在 由于缺乏在体内对这些血统进行特定操作的遗传模型，研究一直在很大程度上 仅限于缺乏适应性免疫系统的免疫缺陷小鼠，目前尚不清楚他们的结论 将适用于普通动物。 该项目建立在我们实验室培育的PLZF-IRES-GFPCre报告小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，并且是 对于正常的发育和功能是必不可少的。本申请的目的是使用PLZF-IRES-GFPCre 小鼠鉴定ILCs的骨髓前体细胞，鉴定其分子特征和遗传学 在体内操纵ILC，以便在已建立的肠道感染模型中确定它们的功能。这个 特异的目的是1)鉴定表达PLZF的ILC谱系的骨髓前体细胞，2)鉴定 它的分子特征；3)建立ILC缺陷小鼠模型，用于肠道感染的研究。这项建议 具有创新性和重大意义，因为它识别了一种新的骨髓前体和一种新的转录 ILC的因素，因为它将为#年感染背景下ILCS的研究产生模型 具有免疫能力的动物。

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.