Embryonic type 3 innate lymphoid cells sense maternal dietary cholesterol to shape mucosal lymphoid organ development

胚胎3型先天淋巴样细胞感知母体膳食胆固醇以形成粘膜淋巴样细胞 器官发育 总结 在怀孕期间，胎儿免疫系统在子宫环境中发育，并依赖于发育的免疫系统。 启动次级淋巴器官（包括脾脏和淋巴结）的器官发生的程序。这 进化保守过程赋予胎儿在出生后协调免疫反应的能力 并对环境中存在的触发器做出反应。 类淋巴组织诱导（LTi）细胞是胎儿先天性淋巴细胞，其在子宫内发育， 负责协调次级淋巴器官的发育。基因突变的人 控制LTi有受损的淋巴结形成，并倾向于粘膜皮肤和全身 感染虽然已经确定LTi功能对于准备具有功能性支架的新生儿至关重要， 启动免疫反应，控制解剖学上不同的肠道次级器官的机制 器官形成尚不清楚。 我们发现，形成肠道派伊尔集合淋巴结（肠道特异性次级淋巴器官）的LTi需要 两个迁移性G蛋白偶联受体（GPCR）GPR183（EBI2）和趋化因子的协调作用 受体CCR6。然而，吸引派尔集合淋巴结LTi的肠解剖位置的性质及其 对LTi分化的影响未知。在这个项目中，我们将测试假设，肠LTi细胞的位置， 在一个分化的“代谢生态位”附近：母亲的饮食提供了成熟的线索，这是 一种由新生儿肠道内的基质细胞产生的胆固醇副产品。 这是一个高风险和高回报的项目，旨在建立胆固醇代谢物的至关重要性 生产和感应胎儿先天淋巴细胞在肠道中的分化。概念基础是独特的， GPCR依赖的成熟和代谢开关在组织中的整合还没有先例 发育过程中固有的淋巴细胞。此外，没有代谢调节密切相关的孕产妇 饮食和胎儿间质细胞介导的，利用相同的线索，将在组织的成人功能 已经被报道了。 这种缺乏先例的做法使该项目具有风险，但如果被证明是准确的，将从根本上改变我们的 了解粘膜固有淋巴细胞对环境变化的感知，并扩展其功能 胆固醇及其副产品在建立和维持健康的免疫系统，特别是在 新生儿

Embryonic type 3 innate lymphoid cells sense maternal dietary cholesterol to shape mucosal lymphoid organ development Summary During pregnancy, the fetal immune system develops in the uterine environment and relies on developmental programs to initiate the organogenesis of secondary lymphoid organs, including spleen and lymph node. This evolutionary conserved process endows the fetus with the ability to orchestrate the immune response after birth and to react to the triggers present in the environment. Lymphoid tissue inducer (LTi) cells are fetal innate lymphocytes that develop during intrauterine life and are deputed to coordinate the development of secondary lymphoid organs. People with mutations in genes controlling LTi have impaired lymph node formation and are predisposed towards mucocutaneus and systemic infection. While it is established that LTi function is critical to prepare the neonate with a functional scaffold to mount immune response, the mechanisms controlling anatomically distinct intestinal secondary organs organogenesis are unclear. We discovered that LTi that form intestinal the Peyer’s patches, gut-specific secondary lymphoid organs, require the coordinated action of two migratory G protein coupled receptor (GPCR) GPR183 (EBI2) and the chemokine receptor CCR6. However, the nature of the intestinal anatomical location attracting Peyer’s patches LTi and its effect on LTi differentiation is unknown. In this project we will test the hypothesis that intestinal LTi cells position themself in proximity of a differentiating “metabolic niche”: maternal diet provides the maturation cues, which is a cholesterol byproduct generated in the neonatal gut by resident stromal cells. This is a high risk and high reward project, designed to establish the critical importance of cholesterol metabolite production and sensing for fetal innate lymphocytes differentiation in the gut. The conceptual basis is unique as there are no precedents for the integration of GPCR- dependent maturation and metabolic switch in tissue resident innate lymphocytes during development. Moreover, no metabolic regulation intimately linked to maternal diet and mediated by fetal stromal cells that exploit same cues that will be generated during tissual adult function have been reported. This lack of precedent makes the project risky, but if proven to be accurate will fundamentally alter our understanding of mucosal innate lymphocytes sensing of environmental alterations and expand the functional domains of cholesterol and its byproducts in building and maintaining a healthy immune system, especially in newborns.