Functional Manipulation of Memory Regulatory T cells in Skin

描述（由申请人提供）：调节性T细胞（Tregs）在组织中建立和维持免疫耐受中起主要作用，偏爱上皮屏障，如皮肤。增强这些细胞的功能对治疗皮肤炎症具有重要的潜力，抑制这些细胞的功能可能对治疗皮肤恶性肿瘤有效。我们最近在小鼠和人类皮肤中都发现了一种独特的treg群体，称为记忆treg （mTreg）。这些细胞是高度活化的抑制因子，在皮肤中稳定维持相对较长时间，并具有增强的减轻炎症的功能能力。本提案的基本主题是功能性剖析皮肤中mtreg利用的主要途径，并开发新的策略，以组织特异性的方式特异性地增强或抑制这些细胞的功能。为了实现这一目标，我们将利用新的技术进步来扰乱人体皮肤中免疫细胞的功能。这是一个高风险、高回报的建议，有可能直接转化为人类疾病。其创新性源于我们将利用新建立的转基因小鼠模型系统为人源化小鼠的实验提供信息，使我们能够有效地将小鼠的发现转化为人类。在基本层面上，我们将获得关于mTregs如何在皮肤中发挥作用的关键机制见解，在翻译层面上，我们将利用这些知识开发炎症性或恶性皮肤病的新治疗策略。

DESCRIPTION (provided by applicant): Regulatory T cells (Tregs) play a major role in establishing and maintaining immune tolerance in tissues, with a predilection for epithelial barriers such as skin. Augmenting the function of these cells has significant potential to treat cutaneous inflammation and inhibiting the function of these cells may prove efficacious in treating cutaneous malignancies. We recently characterized a unique population of Tregs in both murine and human skin, termed memory Tregs (mTreg). These cells are highly activated suppressors that are stably maintained in skin for relatively long periods of time and have enhanced functional capacity to attenuate inflammation. The underlying theme of this proposal is to functionally dissect the dominant pathways utilized by mTregs in skin and develop novel strategies to specifically augment or inhibit the function of these cells in a tissue-specific fashion. To achieve this goal, we will utilize novel technological advances in our ability to disset the function of immune cells in human skin in vivo. This is a high-risk high-reward proposal with the potential for direct translation to human disease. Its innovativeness stems from the fact that we will utilize newly established transgenic mouse model systems to inform experiments in humanized mice, enabling us to effectively and efficiently translate findings from mice to humans. On a basic level, we will gain critical mechanistic insight as to how mTregs function in skin and, on a translational level, we will exploit this knowledge to develop new treatment strategies for inflammatory or malignant skin disease.