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

潜在 TGFb 的调节激活决定白细胞对表皮生态位的占据

• 批准号: 9326142
• 负责人: Daniel H Kaplan
• 金额: $ 44.51万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326142
• 关键词: Ablation; Alopecia Areata; Alpha Cell; Animal Model; Antigens; Autoimmune Diseases; Biology; CD8B1 gene; Categories; Cells; Clinical Trials; Development; Disease; Epidermis; Goals; Grant; Growth; Home environment; Human; Immune; Infection; Inflammation; Inflammatory; Integrins; Interruption; Langerhans cell; Leukocytes; Link; Memory; Modeling; Mus; Patients; Pharmacology; Population; Recruitment Activity; Seeds; Signal Transduction; Simplexvirus; Skin; Stimulus; Surface; T cell response; T memory cell; T-Lymphocyte Subsets; TGFB1 gene; Testing; Therapeutic; Translating; Vaccinia virus; Virus Diseases; Vitiligo; White Blood Cell Count procedure; autocrine; cell motility; cell type; extracellular; fungus; intercellular communication; keratinocyte; lymph nodes; novel; pathogen; residence; response; self-renewal; targeted agent; ultraviolet irradiation

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.

抽象的 皮肤的表皮是一个屏障表面，是抵御多种细菌的前线。 除了提供物理屏障外，表皮还是几类病原体的家园。 长寿的免疫细胞类型最著名的是朗格汉斯细胞 (LC) 和 CD8+ 常驻记忆 T 细胞 (Trm)。 LC 将表皮中获得的抗原转运至淋巴结，并促进淋巴结的发育 针对真菌和可能的其他细胞外病原体的有效 T 细胞反应是最近的研究成果。 记忆 T 细胞亚群，是有效防御继发痘苗病毒所需的 单纯疱疹病毒感染也是导致许多自身免疫性疾病的原因。 尽管这些细胞很重要，但如移植物抗宿主病、白癜风和斑秃。 控制它们在表皮生态位中保留的机制和因素的描述很少。 TGFβ 以潜在形式 (LAP-TGFβ) 从细胞中释放，并被整合素 αvβ6 和 αvβ8 激活。 KC 调节 αvβ6 和 αvβ8 的表达，直接控制角质形成细胞的表皮驻留。 Trm 和 LC 在稳态期间和 UV 照射后的这一观察结果表明了 Trm 和 LC 的可用性。 白细胞驻留的表皮生态位由 TGFβ 的 KC 激活决定，这提出了以下可能性： 活性 TGFβ 的药物减少可用于改变白细胞表皮停留以达到治疗目的 这种竞争性更新的目标是了解白细胞滞留的基本生物学。 表皮生态位，以便合理地将这些发现转化为消耗表皮的方法 我们建议检验疾病状态下的白细胞减少整合素表达的假设。 KC 的区域分离子集响应所有炎症刺激而发生，并导致 我们还将测试表皮 LC 和 Trm 响应其他 KC 的假设。 子集保持整合素表达，从而留下完整的局部生态位 LC 和 Trm，从而允许 LC。 迁移并为新病原体特异的 Trm 打开一些表皮生态位，同时保留 LC 可以重新填充表皮和针对先前遇到的病原体的 Trm 最后，我们将进行测试。 抑制活性 TGFβ 的疗法可减少患者的 LC 和 Trm 并可改善疾病的假设 在白癜风动物模型中。