Parsing cholesterol metabolite regulation of skin immunocytes in children to identify archetypes of human neonatal immune system

项目摘要 产生3型细胞因子（IL-17和IL-22）的淋巴细胞（T3 L）策略性地位于细胞的外周。 粘膜皮肤屏障组织，并作为哨兵的组织扰动的界面与 外界皮肤常驻T3 L在生命早期发育并执行双重功能：生命早期，它们促进 组织健身通过相互作用与肌肉产生滋补IL-17;并在整个生命周期中，他们捍卫 通过快速分泌IL-17对抗病原体，IL-17是将中性粒细胞募集到炎症组织所必需的 强化屏障组织低剂量抗生素引起的早期共生失调 动物（小鼠为E15，人类妊娠24-28周）可导致异常的IL-17产生， 与成年人中观察到的代谢功能障碍有关，包括肥胖。我们最近发现， 小鼠中T3 L的亚群可以感知膳食胆固醇代谢物氧固醇以校准它们的功能。 这些细胞在小鼠出生后立即出现，它们是最快的（先天性）淋巴细胞。 对组织扰动的反应。T3 L对氧固醇的识别是由G蛋白介导的- 偶联受体GPR 183，其在小鼠和人中由所有T3 L表达。GPR 183已经 与人类的牛皮癣、结肠炎和1型糖尿病易感性有遗传联系。在小鼠的早期生活中， 皮肤T3 L亚群介导Toll样受体信号传导下游IL-17驱动的银屑病反应 角质形成细胞这种功能是饮食调节的，并依赖于GPR 183，高胆固醇饮食 导致严重的疾病，相反，素食会抑制IL-17的产生， 减轻疾病的严重程度。这一发现是第一个确定免疫的潜在传感器。 调节肠道外淋巴细胞的饮食代谢物。在人类中，已知T3 L是 在成年人的银屑病中很重要，但在早期免疫系统中几乎一无所知。 这种知识差距的存在，在很大程度上是因为没有系统的普查T3 L及其 儿童皮肤粘膜组织中的相互作用伙伴。这项提案将利用创新的、 无偏见的，互补的单细胞询问方法，以分类所有免疫细胞类型和状态 从婴儿到成年的儿童皮肤中，多参数分层，包括BMI，饮食 习惯和感染史。儿童的皮肤细胞图谱将有助于建立相关性 饮食习惯和高炎症反应倾向之间的关系，由皮肤居民调节 T3L全基因组信息丰富的地图将确定基因网络， 通信和细胞谱系多样化，为组织免疫系统的重要先例 与儿童免疫有关，并加快确定生命早期机制的进展 免疫系统发育。

Project Summary The Type 3 cytokine (IL-17 and IL-22) producing lymphocytes (T3L) are strategically located at the mucocutaneous barrier tissues and serve as sentinels of tissue perturbations at the interface with the outside world. Skin resident T3L develop in early life and perform dual function: Early life, they promote tissue fitness by interacting with commensals to produce tonic IL-17; and throughout life, they defend against pathogens by rapid secretion of IL-17 essential for recruitment of neutrophils to inflamed tissues and fortifying the barrier tissues. Commensal dysbiosis by low dose antibiotics during early life of animals (E15 for mice and 24-28 weeks of gestation in humans) can lead to aberrant IL-17 production and is linked to metabolic dysfunctions observed in adults, including obesity. We discovered recently that a subset of T3L in mice can sense the dietary cholesterol metabolites oxysterols to calibrate their function. These cells arise immediately after birth in mice and they are the fastest (innate-like) lymphoid responders to tissue perturbations. The recognition of oxysterols by T3L is mediated by the G protein- coupled receptor GPR183, which is expressed by all T3L in mice and humans. Gpr183 has been genetically linked to psoriasis, colitis and Type 1 diabetes susceptibility in humans. In mice, early life skin T3L subset mediates IL-17-driven psoriatic responses downstream of Toll-like Receptor signaling in keratinocytes. This function is diet-modulated and dependent on GPR183, with high cholesterol diet leading to severe diseases, and conversely, vegetarian diet dampening IL-17 production and dramatically moderating disease severity. This discovery is the first to identify potential sensors of immune modulatory dietary metabolites on lymphocytes outside the gut. In humans T3L are known to be important in psoriasis in adults, but almost nothing is known about them in early life immune system. This gap in knowledge in large part exists because there is no systematic census of T3L and their interacting partners in mucocutaneous tissues of children. This proposal will fill this gap using innovative, unbiased, complementary single cell interrogation methods to catalogue all immune cell types and states in the skin of children from infancy to adulthood, stratified multi-parametrically, including BMI, dietary habits and infection history. The skin cell atlas of children will be instrumental in establishing correlation between dietary habits and propensity towards hyper inflammatory responses, modulated by skin-resident T3L. The genome-wide information rich map will identify gene networks that govern intercellular communications and cell lineage diversification, setting a major precedent of tissue immune systems relevant for childhood immunity, and accelerate progress towards defining mechanisms of early life immune system development.