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

解析儿童皮肤免疫细胞的胆固醇代谢调节，以确定人类新生儿免疫系统的原型

• 批准号: 10435128
• 负责人: Joonsoo Kang
• 金额: $ 81.69万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-23 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10435128
• 关键词: 1 year old; 3-Dimensional; Adipose tissue; Adult; Animals; Antibiotics; Atlases; Birth; Body mass index; Catalogs; Cell Differentiation process; Cell Lineage; Cells; Censuses; Characteristics; Child; Childhood; Cholesterol; Clinical; Colitis; Couples; Cytokine Receptors; Data; Dermal; Development; Diet; Diet Habits; Dietary Cholesterol; Disease; Disease susceptibility; Dose; Ecology; Environmental Risk Factor; Epithelial; Epithelial Cells; Equilibrium; Etiology; Event; Fetus; Fibroblasts; First Pregnancy Trimester; G-Protein-Coupled Receptors; Generations; Genetic; Genetic Polymorphism; Host Defense; Human; Immune; Immune response; Immune system; Immunity; Infant; Infection; Inflammatory; Inflammatory Response; Insulin-Dependent Diabetes Mellitus; Interleukin-17; Knowledge; Lead; Life; Link; Lymphocyte; Lymphocyte Function; Lymphoid; Lymphoid Cell; Lymphoid Tissue; Maps; Maternal antibody; Mediating; Metabolic; Metabolic dysfunction; Methods; Modeling; Molecular; Mus; Mycoses; Neonatal; Nerve Growth Factors; Neutrophil Infiltration; Normal Cell; Nutritional; Obesity; Organ; Organogenesis; Organoids; Participant; Patients; Pattern; Perinatal; Predisposition; Pregnancy; Production; Proteome; Psoriasis; Receptor Signaling; Recording of previous events; Regulation; Resolution; Sampling; Sentinel; Severity of illness; Skin; Skin Tissue; Structure of parenchyma of lung; Systems Development; T-Lymphocyte; Teenagers; Testing; Thymus Gland; Tissue Sample; Tissues; Toll-like receptors; Vegetarian diet; age related; autoinflammatory; brain tissue; cell type; cytokine; dietary; dysbiosis; fitness; flexibility; gene network; gene regulatory network; genetic manipulation; genome-wide; infancy; innovation; insight; intercellular communication; interleukin-22; keratinocyte; microorganism; neonatal human; neonatal immune system; neonate; novel; pathogen; prevent; programs; receptor; reconstitution; recruit; repaired; response; sensor; sensory mechanism; single cell analysis; transcriptome; transcriptomics

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.

项目概要 产生 3 型细胞因子（IL-17 和 IL-22）的淋巴细胞 (T3L) 战略性地位于 粘膜皮肤屏障组织，并作为与皮肤界面的组织扰动的哨兵 外界。皮肤驻留 T3L 在生命早期发育并发挥双重功能：生命早期，它们促进 通过与共生体相互作用产生补品 IL-17 来实现组织健康；他们一生都在捍卫 通过快速分泌 IL-17 来对抗病原体，该 IL-17 对于将中性粒细胞募集到发炎组织至关重要 并强化屏障组织。生命早期低剂量抗生素造成的共生失调 动物（小鼠 E15 和人类妊娠 24-28 周）可导致 IL-17 产生异常， 与成人中观察到的代谢功能障碍有关，包括肥胖。我们最近发现一个 小鼠中 T3L 的子集可以感知膳食胆固醇代谢物氧甾醇以校准其功能。 这些细胞在小鼠出生后立即出现，它们是最快的（先天性）淋巴样细胞 对组织扰动的反应者。 T3L 对氧甾醇的识别是由 G 蛋白介导的 偶联受体 GPR183，由小鼠和人类的所有 T3L 表达。 Gpr183 已 与人类牛皮癣、结肠炎和 1 型糖尿病易感性存在遗传相关。在小鼠的早期生命中 皮肤 T3L 亚群介导 Toll 样受体信号下游 IL-17 驱动的银屑病反应 角质形成细胞。该功能受饮食调节并依赖于 GPR183，与高胆固醇饮食有关 导致严重疾病，相反，素食会抑制 IL-17 的产生并显着 缓和疾病的严重程度。这一发现首次发现了潜在的免疫传感器 对肠道外淋巴细胞的调节性饮食代谢物。在人类中，T3L 被认为是 在成人牛皮癣中很重要，但对它们在生命早期免疫系统中的作用几乎一无所知。 这种知识差距的存在很大程度上是因为没有对 T3L 及其相关的系统普查。 儿童皮肤粘膜组织中的相互作用伙伴。该提案将利用创新、 无偏见、互补的单细胞询问方法，用于对所有免疫细胞类型和状态进行分类 对儿童从婴儿期到成年期的皮肤进行多参数分层，包括 BMI、饮食 生活习惯及感染史。儿童皮肤细胞图谱将有助于建立相关性 饮食习惯和高炎症反应倾向之间的关系，由皮肤驻留调节 T3L。全基因组信息丰富的图谱将识别控制细胞间质的基因网络 通讯和细胞谱系多样化，开创了组织免疫系统的重要先例 与儿童免疫相关，并加速确定早期生命机制的进展 免疫系统的发育。