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

项目摘要/摘要 组织驻留免疫细胞群对非淋巴组织的功能有广泛的影响 在动态平衡和炎症方面。其中许多免疫细胞首先在高度特异的情况下迁移到组织中 出生后发育时期，此时寄主器官仍在成熟。了解免疫细胞如何 在这一关键发育期对组织的影响可能与糖尿病的发病机制有关 自身免疫性和过敏性疾病，目前许多疾病起源于屏障组织。但是，具体来说， 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 发展仍然难以捉摸。 调节性T细胞(Tregs)是炎症和自身免疫的关键抑制因子，它们建立在 驻留在包括新生儿皮肤在内的许多器官中。这里提供的初步数据表明，新生儿Tregs 通过抑制纤维性间质的生长促进皮肤间质的正常发育 人口。单细胞RNA测序发现了表达T细胞受体的新的皮肤基质群体 细胞衍生的细胞因子，富含炎性细胞因子的表达，并被新生儿抑制 特雷格斯。新生儿Tregs的一过性丢失也会导致皮肤上驻留的Th2细胞的积累。这项建议 将检验这样一种假设，即功能失调的间质发育，通常由Tregs控制，可以产生 致病性Th2细胞的利基环境，增加成年后对未来炎症的易感性。首先， 这些新的皮肤基质细胞类型对炎症信号的反应将从机械上定义(目标1)。 然后，将使用基质特异性细胞因子删除来测试基质如何影响皮肤Th2的积累 细胞(目标2)。最后，这项建议将测试新生儿Tregs的一过性丢失是否会增加易感性 对未来的皮肤炎症(目标3)。来自这些目标的数据将阐明免疫的关键机制 系统影响组织发育并调节出生后时期的炎症，这可能会产生 对早期生命对人类免疫疾病的敏感机制的有价值的见解。 这些研究目标将与全面的培训计划一起进行，以制定 申请者的职业是内科科学家。培训包括有组织的、严格的科学指导 和来自高资质医生-科学家赞助商的技术技能，通过正规的个人进行 以及小组会议、课程、研讨会、杂志俱乐部和部门活动。研究和培训将 在加州大学旧金山分校举行，那里提供了一种出色的免疫学 研究环境和一所优秀的临床培训医学院。

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.