Peripheral mechanisms of homeostasis and tolerance through skin dendritic cells

项目摘要/摘要 免疫系统检查皮肤和其他屏障组织，如肺和肠道，但 导致癌症或自身免疫性疾病的外周免疫失败的机制 都是未知的。树突状细胞(DC)是一种特殊的免疫哨兵，它引导T细胞 容忍或豁免权。DC包含一个丰富的皮肤网络，由几个不同的 但研究不足，在治疗干预方面留下了一个很大的空白。我们有 确定了皮肤中DC的不同属性，这些属性通过向外迁移到排泄来传递信息 淋巴结(LN)。我们发现在炎症期间皮肤迁移性DC可能会引导T细胞产生耐受 通过未知的机制，对免疫进行反调节和控制。这些细胞是唯一的 在人类和小鼠身上进行遗传编程，通过高表达 共有的耐受基因，包括一些已经成功表达的基因，如PD-L1 临床上针对周围组织癌，包括黑色素瘤皮肤癌，结直肠癌 癌症和肺癌。我们假设皮肤DC的动态平衡编程会导致失败 免疫启动导致皮肤癌的早期检测受损。我们发现这些路径是 作为促进自我耐受的治疗目标非常重要(例如在 自身免疫性疾病)或阻断耐受性(在癌症期间提高免疫力)。因为这些 机制是不同的，它们可以与现有的治疗方法相结合，用于 皮肤癌、疫苗科学和炎症性皮肤病的免疫治疗。在2个离散中 这个应用程序将解决皮肤DC的程序性调节和独特的细胞 它们促进小鼠和人类免疫耐受的机制，检查 免疫启动期间的后果和早期皮肤癌的生长。

Project Summary/Abstract The immune system surveys the skin and other barrier tissues such as lung and gut, but mechanisms for failed immunity in the periphery that lead to cancer or autoimmune diseases are unknown. The dendritic cell (DC) is a specialized immune sentinel that directs T cells to tolerance or immunity. DC comprise a rich network in skin consisting of several different populations, but are understudied, leaving a major gap in therapeutic intervention. We have identified distinct properties for DC in skin that relay information by migrating out to the draining lymph node (LN). We find during inflammation skin migratory DC may direct T cells to tolerance by unknown mechanisms, counter-regulating and controlling immunity. These cells are uniquely genetically programed in humans and in mouse to dampen immunity with a high expression of shared tolerance genes, including some genes such as PD-L1 that have been successfully targeted in the clinic for peripheral tissue cancers including melanoma skin cancer, colorectal cancer and lung cancer. We hypothesize homeostatic programming of skin DC leads to failed immune priming leading to impaired early detection of skin cancers. We find these pathways are of great importance as therapeutic targets to promote self-tolerance (such as during autoimmune disease) or to block tolerance (to improve immunity during cancer). Because these mechanisms are distinct they can be combined with current modalities for patients in immunotherapy of skin cancer, vaccine science, and inflammatory skin disease. In 2 discrete aims, this application will address programmatic conditioning of skin DCs and the unique cellular mechanisms by which they promote immune tolerance in both mice and humans, examining consequences during immune priming and early skin cancer growth.