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(T3L)位于 粘膜皮肤屏障组织，并作为组织扰动的哨兵在与 外面的世界。皮肤居民T3L在早期发育并执行双重功能：早期生活，促进 通过与共生体相互作用产生强效的IL-17来适应组织；在整个生命过程中，它们防御 通过快速分泌IL-17来对抗病原体，IL-17是中性粒细胞募集到炎症组织所必需的 并加固屏障组织。早期小剂量抗生素所致的共生失调 动物(小鼠胎龄15岁，人类妊娠24-28周)可导致IL-17的异常产生和 与成年人的代谢功能障碍有关，包括肥胖。我们最近发现，一种 小鼠体内的T3L亚群可以感知饮食中的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，是速度最快的(天生的)淋巴 对组织扰动的响应者。T3L对氧合甾醇的识别是由G蛋白介导的。 偶联受体GPR183，在小鼠和人的T3L中均有表达。GPR183已被 基因上与牛皮癣、结肠炎和人类1型糖尿病易感性有关。在小鼠身上，早期生命 皮肤T3L亚群介导Toll样受体信号转导下游IL-17诱导的银屑病反应 角质形成细胞。这种功能是饮食调节的，依赖于GPR183，高胆固醇饮食 导致严重的疾病，反过来，素食抑制IL-17的产生并显著 缓解疾病的严重程度。这一发现是第一次识别潜在的免疫传感器。 肠道外淋巴细胞上的调节性膳食代谢物。在人类中，已知T3L是 在成人银屑病中很重要，但对早期生命免疫系统几乎一无所知。 这种知识差距的存在在很大程度上是因为没有对T3L和他们的学生进行系统的普查 儿童皮肤粘膜组织中的相互作用伙伴。该提案将使用创新的、 对所有免疫细胞类型和状态进行分类的无偏见、互补性的单细胞询问方法 在儿童从婴儿期到成年期的皮肤中，多参数分层，包括BMI，饮食 习惯和感染史。儿童皮肤细胞图谱将有助于建立相关性 饮食习惯和高炎性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图谱将识别支配细胞间的基因网络 通信和细胞谱系多样化，开创了组织免疫系统的重大先例 与儿童免疫相关，并加快在确定早期生命机制方面的进展 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.