Elucidating the Fundamental Biology of Memory Regulatory T cells in Skin

描述(申请人提供)：调节性T细胞(Treg)在建立和维持组织中的免疫耐受中起主要作用，偏向于皮肤等上皮屏障。增强这些细胞的功能在治疗皮肤炎症方面具有重要的潜力，而抑制这些细胞的功能可能被证明在治疗皮肤恶性肿瘤方面是有效的。我们最近在小鼠和人的皮肤中鉴定了一种独特的Tregs种群，称为记忆Tregs(MTreg)。这些细胞是高度激活的抑制物，可以在皮肤中稳定地保持相对较长的一段时间，并具有增强的消炎功能。这项提议的基本主题是从功能上剖析mTregs在皮肤中利用的主要途径，并开发新的策略，以组织特异性的方式具体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，在体内扰乱人类皮肤中免疫细胞的功能。这是一项高风险、高回报的提议，有可能直接转化为人类疾病。它的创新性源于这样一个事实，即我们将利用新建立的转基因小鼠模型系统来为人性化小鼠的实验提供信息，使我们能够有效和高效地将研究结果从小鼠转化为人类。在基础水平上，我们将获得关于mTregs如何在皮肤中发挥作用的关键机制方面的见解，在翻译水平上，我们将利用这些知识来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.