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

摘要 皮肤的表皮是一个屏障表面，它是抵御各种 潜在的病原体。除了提供物理屏障外，表皮还是几种类型的 长寿免疫细胞类型，尤其是朗格汉斯细胞(LC)和CD8+驻留记忆T细胞(Trm)。 从表皮获得的LC转运抗原到淋巴结，在那里它们促进肿瘤的发展 有效的T细胞对真菌和可能的其他细胞外病原体的反应。TRM细胞是最近出现的一种细胞 有效预防二次痘苗病毒所需的记忆T细胞亚群 和单纯疱疹病毒感染。LC和Trm也是许多自身免疫性疾病的罪魁祸首 移植物对抗宿主病、白癜风和斑秃。尽管这些细胞很重要，但 机制(S)和控制它们在表皮壁龛中保留的因素一直描述得很少。 转化生长因子β以潜伏形式(LAP-转化生长因子β)从细胞中释放出来，并被整合素αvβ6和αvβ8激活。 角质形成细胞(KC)。KC对α-v-β-6和α-v-β-8的调节表达直接控制表皮细胞的滞留 稳态期间和紫外线照射后的Trm和LC都是如此。这一观察结果表明， 转化生长因子β的KC活性决定了白细胞滞留的表皮生态位 药物降低活性转化生长因子β可用于改变白细胞在表皮的滞留状态 利益。这种竞争性更新的目标是了解白细胞在体内滞留的基本生物学 以合理地将这些发现转化为消耗表皮的方法 处于疾病状态的白细胞。我们建议通过以下方式检验整合素表达减少的假设 区域分离的KC亚群发生在对所有炎症刺激的反应中，并导致 表皮Lc和Trm.我们还将测试假设，在对炎性刺激的反应中，其他KC 亚群保持整合素的表达，从而保持完整的局部生态位Lc和Trm。这将允许LC 迁移并打开一些针对Trm的新病原体的表皮生态位，同时也保留LC 这可以重新填充以前遇到的病原体特异的表皮和Trm。最后，我们将测试 抑制活性转化生长因子β治疗可降低患者LC和TRM并可改善疾病的假说 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.