The role of regulatory T cells in early-life development and immunity of the skin

调节性 T 细胞在生命早期发育和皮肤免疫中的作用

• 批准号: 10430113
• 负责人: Ian Boothby
• 金额: $ 5.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430113
• 关键词: Ablation; Adipocytes; Adult; Affect; Allergic Disease; Antibodies; Area; Autoimmune Diseases; Autoimmunity; Automobile Driving; Birth; California; Cell Cycle; Cells; Childhood; Choristoma; Clinical; Confocal Microscopy; Cues; Data; Defect; Development; Disease; Environment; Event; Fibrosis; Future; Genetic Transcription; Goals; Group Meetings; Homeostasis; Human; Immune; Immune System Diseases; Immune Tolerance; Immune system; Immunity; Immunologics; Immunology; In Situ; Individual; Inflammation; Inflammatory; Interferon Type II; Interleukin-13; Interleukin-18; Journals; Kinetics; Life; Location; Lymphocyte; Lymphocyte Activation; Lymphocyte Count; Maintenance; Mediating; Mentorship; Metabolism; Modeling; Mus; Neonatal; Organ; Pathogenesis; Pathogenicity; Peripheral; Physicians; Play; Population; Predisposition; Regulatory T-Lymphocyte; Research; Research Training; Role; San Francisco; Scientist; Signal Transduction; Skin; Source; Stromal Cells; Structure; T-Cell Receptor; T-Lymphocyte; TSLP gene; Technical Expertise; Testing; Th2 Cells; Time; Tissues; Training; Universities; Work; autoimmune pathogenesis; autoreactivity; candidate marker; career; critical developmental period; critical period; cytokine; experimental study; genetic signature; immunoregulation; infancy; innovation; insight; medical schools; neonatal mice; neonate; novel; pathogen; postnatal; postnatal development; postnatal period; prevent; recruit; residence; response; single-cell RNA sequencing; skin organogenesis; stem cell differentiation; stem cells; subcutaneous; tissue repair

PROJECT SUMMARY/ABSTRACT Tissue-resident immune cell populations have extensive effects on the function of nonlymphoid tissues in homeostasis and inflammation. Many of these immune cells first migrate to tissues during highly specific periods of postnatal development when their host organs are still maturing. Understanding how immune cells influence tissues during this critical developmental period is likely to be relevant to the pathogenesis of autoimmune and allergic disease, many of which originate in barrier tissues at this time. However, specific cellular mechanisms by which immune cells interact with parenchymal and stromal cells during postnatal development remain elusive. Regulatory T cells (Tregs) are critical suppressors of inflammation and autoimmunity that establish residence in many organs including neonatal skin. Preliminary data presented herein show that neonatal Tregs enforce normal development of the skin stroma by suppressing the outgrowth of a fibrosis-like stromal population. Single cell RNA sequencing revealed novel skin stromal populations that express receptors for T cell-derived cytokines, are enriched for expression of inflammatory cytokines, and are inhibited by neonatal Tregs. Transient loss of neonatal Tregs also leads to the accumulation of skin-resident Th2 cells. This proposal will test the hypothesis that dysfunctional stromal development, normally held in check by Tregs, can create niches for pathogenic Th2 cells that increase the susceptibility to future inflammation in adulthood. First, the response of these novel skin stromal celltypes to inflammatory cues will be mechanistically defined (Aim 1). Stromal-specific cytokine deletion will then be used to test how the stroma affects the accumulation of skin Th2 cells (Aim 2). Lastly, this proposal will test whether transient loss of neonatal Tregs increases the susceptibility to future skin inflammation (Aim 3). Data from these aims will elucidate key mechanisms by which the immune system influences tissue development and regulates inflammation in the postnatal period, which may yield valuable insights into the mechanisms of early life sensitization to human immunological diseases. These research goals will be conducted in conjunction with a comprehensive training plan to develop the applicant’s career as a physician-scientist. Training includes structured, rigorous mentorship in scientific and technical skills from a highly qualified physician-scientist sponsor, carried out through regular individual and group meetings, classes, seminars, journal clubs, and departmental events. Research and training will take place at the University of California, San Francisco, which offers both an outstanding immunology research environment and an excellent medical school for clinical training.

项目总结/摘要 组织驻留免疫细胞群体对非淋巴组织的功能具有广泛的影响 体内平衡和炎症。许多这些免疫细胞首先迁移到组织中， 出生后的发育期，此时它们的宿主器官仍在发育成熟。了解免疫细胞如何 在这个关键的发育时期影响组织可能与发病机制有关， 自身免疫性和过敏性疾病，其中许多起源于屏障组织在这个时候。但具体 出生后免疫细胞与实质细胞和基质细胞相互作用的细胞机制 发展仍然遥遥无期。 调节性T细胞（TCFs）是炎症和自身免疫的关键抑制因子， 在包括新生儿皮肤在内的许多器官中存在。本文提供的初步数据显示， 通过抑制纤维变性样基质的生长来促进皮肤基质的正常发育 人口单细胞RNA测序揭示了表达T细胞受体的新型皮肤基质群 细胞衍生的细胞因子，富含炎性细胞因子的表达，并被新生儿 你好新生儿TdR的短暂丧失也导致皮肤驻留Th 2细胞的积累。这项建议 将测试这一假设，即功能失调的基质发育，通常由TdR控制，可以创造 致病性Th 2细胞的小生境，增加成年后对未来炎症的易感性。一是 这些新的皮肤基质细胞类型对炎性信号的反应将被机械地定义（目的1）。 然后将使用基质特异性细胞因子缺失来测试基质如何影响皮肤Th 2的积累 细胞（目标2）。最后，该提案将测试新生儿TdR的短暂丧失是否会增加易感性。 未来的皮肤炎症（目标3）。来自这些目标的数据将阐明免疫系统的关键机制。 系统影响组织发育并调节出生后时期的炎症， 对人类免疫性疾病的早期生命致敏机制有价值的见解。 这些研究目标将与一个全面的培训计划一起进行， 申请人的职业生涯作为一个物理学家，科学家。培训包括在科学领域有组织、严格的指导， 和技术技能从一个高素质的医生，科学家赞助商，通过定期个人进行 以及小组会议、课程、研讨会、期刊俱乐部和部门活动。研究和培训将 发生在加州大学，旧金山弗朗西斯科，既提供了一个杰出的免疫学 研究环境和优秀的临床培训医学院。