Adipose-tissue Tregs: important players in immunological control of metabolism

Foxp 3 + CD 4+调节性T细胞（TCRs）控制大多数类型的免疫应答。最近，不同的 还发现了有助于维持局部稳态的组织定位TdR的隔室。这些如此- 称为“组织-T细胞”的细胞具有不同的转录组、TCR库和生长/存活因子依赖性， 与淋巴器官的胸腺和其他组织中的胸腺相比。组织-胸腺调节非免疫 通过影响先天性和适应性免疫细胞， 局部间质和实质细胞。一个典型的组织-Treg隔室，首先由PI的实验室报告 在2009年，在内脏脂肪组织（VAT）中发现，特别是瘦小鼠的内脏VAT（eVAT）库。 依赖于脂肪生成的最高调节因子PPARγ的有效增加和功能， 有助于确保局部和全身代谢，特别是胰岛素敏感性。这一重要功能反映了 直接eVAT-Treg影响局部免疫细胞和eVAT驻留的免疫细胞促进间充质细胞 基质细胞（VmSCs）。该项目的重点是新发现的eVAT TdR功能。我们 主要来自转录组学分析和体外脂肪生成测定的初步数据表明， 它们控制基质驻留脂肪细胞前体细胞分化成成熟脂肪细胞（和 潜在的脂肪细胞更新和纤维化）。此外，这些数据表明，制瘤素M（OSM）作为一种潜在的 这些影响的中介。本拟议项目的主要目标是阐明 eVAT细胞和脂肪细胞前体之间的通讯途径。我们建议： (1)为了确定由eVAT-TdR产生的OSM在多大程度上负责它们对基质的限制， 常驻脂肪细胞前体。该目标解决了验证我们的转录组学和体外实验的需要。 脂肪生成数据与体内检查。 (2)评价衰老对eVAT-Treg控制局部炎症和脂肪生成的影响。差异 在文献中，这意味着eVAT TdR的影响可能在衰老小鼠与老年小鼠中非常不同。我们建议 在对特异性缺乏eVAT-T细胞的小鼠进行头对头比较中评估这一概念。 (3)确定eVAT-Treg控制脂肪细胞分化是否以及如何显示性二型性。 雄性和雌性啮齿动物和人类在脂肪组织的沉积和功能方面存在差异。最近的一份报告 (on PI的实验室合作）强调了在IL-33产生，免疫细胞， 促进VmSC，导致性腺VAT累积的二型性。我们的初步数据显示 在脂肪细胞动力学中也是如此，这是本目标的重点。 在成功完成这个拟议项目后，我们应该知道eVAT-THERM在什么情况下调节 脂肪细胞动力学以及它们是如何做到的。这代表了eVAT标签的一个新功能， 组织调节性T细胞控制干/祖细胞活性的新主题。

Foxp3+CD4+ regulatory T cells (Tregs) control most types of immune responses. Recently, distinct compartments of tissue-localized Tregs that help maintain local homeostasis were also discovered. These so- called “tissue-Tregs” have transcriptomes, TCR repertoires and growth/survival factor dependencies that differ from those of lymphoid-organ Tregs and of Tregs in other tissues. Tissue-Tregs regulate non-immunological processes such as metabolism and regeneration via influences on innate and adaptive immunocytes as well as on local stromal and parenchymal cells. A paradigmatic tissue-Treg compartment, first reported by the PI's lab in 2009, is that found in visceral adipose tissue (VAT), especially the epidydimal VAT (eVAT) depot of lean mice. eVAT Tregs, which depend on the supreme regulator of adipogenesis, PPARγ, for effective accrual and function, help assure local and systemic metabolism, notably insulin sensitivity. This important function is known to reflect direct eVAT-Treg influences on local immunocytes and on eVAT-resident, immunocyte-promoting mesenchymal stromal cells (VmSCs). The focus of this proposed project is on a newly discovered function of eVAT Tregs. Our preliminary data, primarily derived from transcriptomic analyses and in vitro adipogenesis assays, indicate that they control the differentiation of stroma-resident adipocyte precursor cells into mature adipocytes (and potentially adipocyte turnover and fibrosis). Moreover, these data point to Oncostatin M (OSM) as a potential mediator of these influences. THE MAJOR GOAL OF THIS PROPOSED PROJECT IS TO ELUCIDATE THE AVENUES OF COMMUNICATION BETWEEN eVAT Tregs AND ADIPOCYTE PRECURSORS. We propose: (1) To determine the extent to which OSM production by eVAT-Tregs is responsible for their constraint of stroma- resident adipocyte precursors. This Aim addresses the need to validate our transcriptomic and in vitro adipogenesis data with in vivo examinations. (2) To evaluate the effects of aging on eVAT-Treg control of local inflammation and adipogenesis. Discrepancies in the literature imply that the impact of eVAT Tregs may be very different in aging vs old mice. We propose to evaluate this notion in a head-to-head comparison of mice specifically lacking eVAT-Tregs or not. (3) To determine whether and how eVAT-Treg control of adipocyte differentiation shows sexual dimorphism. Male and female rodents and humans differ in the deposition and function of their adipose tissue. A recent report (on which the PI's lab collaborated) highlights a male:female dichotomy in IL-33-producing, immunocyte- promoting VmSCs, leading to a dimorphism in gonadal VAT accrual. Our preliminary data uncovered a difference in adipocyte dynamics as well, which is the focus of this Aim. Upon successful completion of this proposed project, we should know in what contexts eVAT-Tregs regulate adipocyte dynamics and how they do so. This represents a novel function of eVAT Tregs, one that fits within the emerging theme of tissue-Treg control of stem/progenitor cell activities.