Peripheral mechanisms of homeostasis and tolerance through skin dendritic cells

项目总结/摘要 免疫系统检查皮肤和其他屏障组织，如肺和肠，但 导致癌症或自身免疫性疾病的外周免疫失败的机制 是未知的。树突状细胞（DC）是一种专门的免疫哨兵，它指导T细胞 容忍或豁免。DC在皮肤中包含一个丰富的网络， 这是一个非常重要的问题，因为它在人口中，但研究不足，在治疗干预方面留下了一个重大空白。我们有 确定皮肤中DC的不同属性，通过迁移到引流区来传递信息 淋巴结（LN）。我们发现在炎症过程中，皮肤迁移性DC可能指导T细胞耐受 通过未知的机制，反调节和控制免疫力。这些细胞是独一无二的 在人类和小鼠中进行基因编程，以高表达 共享的耐受基因，包括一些基因，如PD-L1，已经成功地 在临床上靶向治疗外周组织癌症，包括黑色素瘤皮肤癌、结肠直肠癌 癌症和肺癌。我们假设皮肤DC的稳态编程导致失败的 导致皮肤癌早期检测受损的免疫引发。我们发现这些通路 作为促进自身耐受性的治疗靶点是非常重要的（例如在 自身免疫性疾病）或阻断耐受性（以提高癌症期间的免疫力）。因为这些 机制是不同的，它们可以与当前的模式相结合， 皮肤癌免疫治疗、疫苗科学和炎症性皮肤病。在2个离散 目的，该应用程序将解决皮肤DC的程序性调节和独特的细胞调节。 它们促进小鼠和人类免疫耐受的机制， 在免疫引发和早期皮肤癌生长过程中的后果。

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.