Elucidating the Fundamental Biology of Memory Regulatory T cells in Skin

描述（由申请人提供）：调节性T细胞（TCRs）在组织中建立和维持免疫耐受性方面发挥主要作用，偏好上皮屏障，如皮肤。增强这些细胞的功能具有治疗皮肤炎症的显著潜力，并且抑制这些细胞的功能可以证明在治疗皮肤恶性肿瘤中有效。我们最近在小鼠和人皮肤中表征了一个独特的Tclad群体，称为记忆Tclad（mTreg）。这些细胞是高度活化的抑制因子，其在皮肤中稳定维持相对长的时间段，并且具有增强的功能能力以减轻炎症。该提案的基本主题是从功能上剖析皮肤中mTdR所利用的主要途径，并开发新的策略以组织特异性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，在我们的能力，扰乱人体皮肤中的免疫细胞在体内的功能。这是一个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。在基本水平上，我们将获得关键的机制洞察力，以mTdR如何在皮肤中发挥作用，并在翻译水平上，我们将利用这些知识来开发新的治疗策略炎症或恶性皮肤病。

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.