Regulated Activation of Latent-TGFb Determines Leukocyte Occupancy of the Epidermal Niche

摘要 皮肤的表皮是屏障表面，其充当抵抗多种多样的炎症的前线。 潜在的病原体除了提供物理屏障外，表皮还是几种类型的细胞的家园。 长寿的免疫细胞类型，最值得注意的是朗格汉斯细胞（LC）和CD 8+驻留记忆T细胞（Trm）。 LC将表皮中获得的抗原转运到淋巴结，在淋巴结中它们促进 针对真菌和可能的其他细胞外病原体的有效T细胞应答。Trm细胞是最近 有效保护免受二次牛痘病毒所需的记忆T细胞的受欢迎的亚群 和单纯疱疹病毒感染。LC和Trm也负责许多自身免疫性疾病， 如移植物抗宿主病、白癜风和斑秃。尽管这些细胞的重要性， 控制它们在表皮小生境中保留的机制和因素描述得很少。 TGFβ以潜伏形式（LAP-TGFβ）从细胞中释放，并被整合素αvβ6和αvβ8激活， 角质形成细胞（KC）。KC对αvβ6和αvβ8表达的调节直接控制了表皮细胞的驻留， Trm和LC在稳态期间和UV照射后。这一观察表明， 白细胞驻留的表皮生态位是由KC激活TGFβ决定的， 活性TGFβ的药理学减少可用于改变白细胞表皮驻留，以治疗 效益这种竞争性更新的目标是了解白细胞保留在细胞内的基本生物学。 为了合理地将这些发现转化为消耗表皮的方法， 疾病状态下的白细胞。我们建议测试的假设，减少表达的整合素， KC的区域分离的亚群响应于所有炎症刺激而发生，并导致 表皮LC和Trm.我们还将检验这一假设，即在对炎症刺激的反应中， 亚群维持整联蛋白表达，从而完整地保留局部小生境LC和Trm。这将使LC 迁移并为新病原体特异性Trm打开一些表皮生态位，同时还保留LC 它可以重新填充表皮和Trm，对以前遇到的病原体具有特异性。最后，我们将测试 抑制活性TGFβ的疗法可降低患者的LC和Trm并可改善疾病的假设 在白癜风的动物模型中。

Abstract The epidermis of the skin is a barrier surface that serves as the front line of defense against a diverse array of potential pathogens. In addition to providing a physical barrier, the epidermis is home to several categories of long-lived immune cell types most notably Langerhans cells (LC) and CD8+ resident memory T cells (Trm). LC transport antigen acquired in the epidermis to the lymph node where they promote the development of effective T cell responses against fungi and likely other extracellular pathogens. Trm cells are a recently appreciated subset of memory T cell that are required for efficient protection against secondary Vaccinia virus and Herpes Simplex virus infections. LC and Trm are also responsible for many autoimmune diseases such as graft vs. host disease, vitiligo, and alopecia areata. Despite the importance of these cells, the mechanism(s) and factors governing their retention in the epidermal niche have been poorly described. TGFβ is released from cells as a latent form (LAP-TGFβ) and is activated by the integrins αvβ6 and αvβ8 on keratinocytes (KC). The regulated expression of αvβ6 and αvβ8 by KC directly controls epidermal residence of both Trm and LC during steady-state and after UV irradiation. This observation that the availability of the epidermal niche for leukocyte residence is determined by KC activation of TGFβ raises the possibility that pharmacologic reduction of active TGFβ could be used to alter leukocyte epidermal residence to therapeutic benefit. The goal of this competitive renewal is understand the basic biology of leukocyte retention within the epidermal niche in order to rationally translate these findings into approaches that deplete epidermal leukocytes in disease states. We propose to test the hypothesis that reduced expression of integrins by regionally segregated subsets of KC occurs in response to all inflammatory stimuli and results in loss of epidermal LC and Trm. We will also test the hypothesis that in response to inflammatory stimuli other KC subsets maintain integrin expression thereby leaving intact a local niche LC and Trm. This would allow for LC migration and open some of the epidermal niche for Trm specific for the new pathogen while also retaining LC that can repopulate the epidermis and Trm specific to previously encountered pathogens. Finally, we will test the hypothesis that therapies inhibiting active TGFβ reduce LC and Trm in patients and can ameliorate disease in an animal model of vitiligo.