Muscle Tregs in health and disease

除了抵御微生物挑战的主要功能外，免疫系统还发挥着重要作用 在维护组织的动态平衡方面。巨噬细胞很早就被认为是进行这种继发性运动 在过去的几年里，人们对Foxp3+CD4+的含义越来越感兴趣 体内平衡过程中的调节性T细胞(或Tregs)。例如，数字中的唯一Treg隔间 在急性或慢性损伤后，实质组织促进局部修复/再生--即使在斑马鱼身上也是如此！ 骨骼肌树突状细胞是一个典型的促再生调节性T细胞群体。第一 本实验室在2012年报道，急性损伤后肌肉Tregs迅速增加，不同于淋巴器官 表达增强的T细胞，组织适应的转录组，独特的克隆性扩增的T细胞 受体谱系，以及生长/存活因子依赖。一个耐人寻味的轴，在上一次 资金周期，需要伤害性神经元产生多肽CGRP；它引起IL-33的产生 基质细胞；这反过来又促进了局部Treg的积累。肌束对人体产生多方面的影响 组织修复的过程-在淋巴细胞和非淋巴细胞在早期，促炎， 和晚期，支持再生的阶段。这一广泛的活动范围突出表明有必要超越当前 肌肉的静态图像-Treg的表型和功能，以获得跨越整个过程的动态视图。 损伤后1-14天肌-Treg室的时间单细胞RNAseq数据 (在上一次融资周期中生成的)显示了五种不同的亚型，它们随着时间的推移而兴衰： 循环、最近激活、RoRγ+、T-bet+和GATA3+(或修复性)。我们的长期目标是 了解五种肌肉-Treg亚型如何相互结合以及如何与相邻的肌肉结合 淋巴和非淋巴细胞促进肌肉再生。我们的总体假设是 个别亚型出现和/或扩展以处理在 修复/再生过程。特别是，这一拟议项目旨在： 1.鉴定γ+骨骼肌树的来源。 2.确定(S)RoRγ+Treg在肌肉有效修复/再生中的关键作用。 3.确定内源性CGRP是否协调肌肉MSCs增加IL-33的产生和 随之而来的是修复性(GATA3+)肌肉Treg亚型的扩张。 这些研究的完成将为我们提供更准确和细微的Treg活动图景 在肌肉再生过程中。潜在的治疗应用有很多：灾难性的伤口愈合，锻炼- 诱发性损伤、年龄相关性骨质疏松症、肌营养不良症、自身免疫性肌炎和慢性肌肉 感染。

Beyond its primary function of repelling microbial challenges, the immune system plays important roles in safeguarding tissue homeostasis. Macrophages have long been recognized to exercise such secondary functions and, over the past several years, there has been growing interest in the implication of Foxp3+CD4+ regulatory T cells (or Tregs) in homeostatic processes. For example, unique Treg compartments in a number of parenchymal tissues promote local repair/regeneration after acute or chronic injury – even in zebrafish! Skeletal-muscle Tregs serve as a paradigmatic pro-regenerative regulatory T cell population. First reported by our lab in 2012, muscle Tregs increase rapidly after acute injury, differing from lymphoid-organ Tregs in their elevated representation, tissue-adapted transcriptome, distinct – clonally expanded – T cell receptor repertoire, and growth/survival factor dependencies. One intriguing axis, discovered during the last funding-cycle, entails nociceptive neuron production of the peptide, CGRP; which elicits IL-33 production from stromal cells; which, in turn, promotes local Treg accumulation. Muscle Tregs exert multiple influences along the course of tissue repair – on both lymphoid and non-lymphoid cells during both the early, pro-inflammatory, and late, pro-regenerative, phases. This broad range of activities highlights the need to go beyond the current static image of muscle-Treg phenotype and function to obtain a dynamic view spanning the entire process. Temporal single-cell RNAseq data on the muscle-Treg compartment from 1-14 days post-injury (generated during the last funding-cycle) revealed five distinct subtypes that waxed and waned over time: circulating, recently activated, RORγ+, T-bet+ and GATA3+ (or reparative). Our long-term goal is to understand how the five muscle-Treg subtypes integrate with each other and with neighboring lymphoid and non-lymphoid cells to promote muscle regeneration. Our overall hypothesis is that individual subtypes emerge and/or expand to deal with particular biological issues that arise during the repair/regeneration process. In particular, this proposed project aims to: 1. Identify the provenance of RORγ+ skeletal-muscle Tregs. 2. Determine what critical role(s) RORγ+ Tregs play in effective muscle repair/regeneration. 3. Determine whether endogenous CGRP orchestrates increased IL-33 production by muscle MSCs and consequent expansion of the reparative (GATA3+) muscle-Treg subtype. Completion of these studies will provide us with a more accurate and nuanced picture of Treg activities during muscle regeneration. Potential therapeutic applications are many: catastrophic wound healing, exercise- induced damage, age-related sarcopenias, muscular dystrophies, autoimmune myositides and chronic muscle infections.