Muscle Tregs in health and disease

项目总结/摘要 Foxp 3 + CD 4+调节性T（Treg）细胞控制大多数类型的免疫应答，影响免疫应答的活性。 先天和适应性细胞类型。越来越多的证据表明，特殊类别的THEORY也调节非- 非免疫细胞中的免疫过程-以及因此的生物体内平衡。的 迄今为止最好表征的例子是位于内脏脂肪组织中的Foxp 3 + CD 4+群体， 调节局部和全身代谢指标。最近，在小鼠中鉴定了不同的Treg群体， 骨骼肌肌肉T细胞在局部CD 4 + T细胞区室中高度富集，并且具有 独特的T细胞受体库和转录组。它们调节肌肉的再生， 急性和慢性损伤，影响浸润先天细胞的行为以及影响肌肉祖细胞 细胞，至少部分通过分泌生长/存活因子双调蛋白。类似的人口 Foxp 3 + CD 4 + T细胞已在人类中鉴定，在杜氏肌营养不良症患者中富集。 初步数据提供了强有力的证据，表明IL-33控制Treg在受损骨骼肌中的积累。为 例如，这种细胞因子在老年小鼠的肌肉中缺乏，就像TGFAP一样，部分解释了这种细胞因子在老年小鼠的肌肉中缺乏。 老年动物的肌肉修复特征;这种细胞因子的实验补充与 损伤显著改善肌肉修复/再生。IL-33在肌肉中具有有趣的表达模式： 主要存在于脂肪/成脂祖细胞中，通常（但不总是）与原型细胞密切相关。 神经结构，如神经束和肌梭。本拟议项目的主要目标是 阐明急性炎症过程中TGFAP和IL-33产生细胞之间的细胞和分子相互作用， 慢性肌肉损伤这一目标将在三个具体目标的框架内实现：1）描绘一个 骨骼肌中IL-33产生细胞的更精确图像; 2）评估IL-33产生细胞的功能相关性， IL-33-生产者和肌肉中的神经结构之间的物理联系，以及3）探索IL-33-生产者和肌肉中的神经结构之间的作用。 33例慢性肌肉疾病。这些目标的成功实现将促进我们的理解， 和潜在的治疗，包括减少肌肉质量，功能和 修复老年人、肌营养不良症如杜氏肌营养不良症和潜在的肌萎缩性 侧索硬化症。

PROJECT SUMMARY/ABSTRACT Foxp3+CD4+ regulatory T (Treg) cells control most types of immune responses, influencing the activities of both innate and adaptive cell-types. Evidence is mounting that special classes of Tregs also regulate non- immunological processes in non-immunological cells – and, as a consequence, organismal homeostasis. The best characterized example to date is a Foxp3+CD4+ population that resides in visceral adipose tissue and regulates local and systemic metabolic indices. Recently, a distinct Treg population was identified in murine skeletal muscle. Muscle Tregs are highly enriched within the local CD4+ T cell compartment, and have a distinctive T cell receptor repertoire and transcriptome. They regulate muscle regeneration in response to both acute and chronic injury, affecting the behavior of infiltrating innate cells as well as impacting muscle progenitor cells, at least in part via secretion of the growth/survival factor, Amphiregulin. An analogous population of Foxp3+CD4+ T cells has been identified in humans, enriched in patients with Duchenne muscular dystrophy. Preliminary data provide strong evidence that IL-33 controls Treg accumulation in injured skeletal muscle. For example, this cytokine is deficient in muscles of geriatric mice, as are Tregs, partially explaining the poor muscle repair characteristic of old animals; and this cytokine’s experimental supplementation coincident with injury significantly improves muscle repair/regeneration. Il-33 has an intriguing pattern of expression in muscle: primarily in fibro/adipogenic progenitor cells, often (though not always) in close association with archetypal nerve structures, such as nerve bundles and muscle spindles. The major goal of this proposed project is to elucidate the cellular and molecular interactions between Tregs and IL-33-producing cells during acute and chronic muscle injury. This goal will be addressed in the framework of three Specific Aims: 1) to paint a more precise picture of IL-33-producing cells in skeletal muscle; 2) to evaluate the functional relevance of the physical association between IL-33-producers and nerve structures in muscle, and 3) to explore the role of IL- 33 in a chronic muscle disease. Successful completion of these Aims stands to advance our understanding, and potential treatment, of several muscle pathologies – including the reduced muscle mass, function and repair of the aged, muscular dystrophies such as Duchenne muscular dystrophy, and potentially Amyotrophic Lateral Sclerosis.