CTLA4 as a guardian of the melanocyte stem cell immune privilege: Role in vitilligo

CTLA4 作为黑素细胞干细胞免疫特权的守护者：在白癜风中的作用

• 批准号: 10116287
• 负责人: M. Raza Zaidi
• 金额: $ 16.91万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116287
• 关键词: Address; Affect; Affinity; Antigen-Presenting Cells; Antigens; Area; Autoimmune Diseases; Binding; Biological Markers; CD28 gene; CD8-Positive T-Lymphocytes; CD80 gene; CD86 gene; CTLA4 gene; Cell Compartmentation; Cell surface; Cells; Child; Coculture Techniques; Complex; Cytotoxic T-Lymphocytes; Data; Disease; Environmental Risk Factor; Etiology; Exhibits; Failure; Genes; Genetic Predisposition to Disease; Goals; Hair; Hair follicle structure; Homeostasis; Human; Immune; Immune system; Interferon Type II; Knock-out; Knockout Mice; Lead; Ligands; LoxP-flanked allele; Maintenance; Mediating; Melanoma Cell; Mental Health; Molecular; Mus; Normal Cell; Patients; Phase; Pigments; Play; Predisposition; Quality of life; Regulatory T-Lymphocyte; Reporting; Role; Sampling; Signal Transduction; Skin; Skin Pigmentation; Skin Tissue; Surface; T cell regulation; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Time; Vitiligo; anergy; autoimmune pathogenesis; autoreactivity; cell type; chemokine; cytokine; cytotoxic CD8 T cells; effector T cell; experimental study; melanocyte; mouse model; negative affect; novel; overexpression; receptor; recruit; response; self esteem; stem cells; treatment strategy

Project Summary Vitiligo is the most common skin depigmentation disorder that affects 65-95 million people worldwide. The disease is characterized by a selective loss of epidermal melanocytes leading to loss of skin pigmentation in patches that can be localized to small areas or spread widely. This disease causes not only disfigurement, but also affects the patients’ psychological health with respect to self-esteem and quality of life. Current strategies for treatment of vitiligo are only moderately effective at best, are not durable, and are practically and financially burdensome. Vitiligo is a complex disease with intricate interactions among and contributions from the immune system, genetic predisposition, and environmental factors. Nevertheless, vitiligo is fundamentally an autoimmune disease in which CD8+ T cells (also known as cytotoxic T lymphocytes or CTLs) play the key effector role leading to destruction of melanocytes. These skin resident T cells must be tightly controlled, lest they get inadvertently activated to become auto-reactive. This control is achieved through the regulatory T cells (Tregs), which dampen the CTL responses. It is, however, unknown whether the melanocytes and/or melanocyte stem cells themselves play an active role in protecting themselves against a possible CTL attack via inherent self-immunoprotective mechanism(s). Here we propose such a novel mechanism for the first time. Cytotoxic T lymphocyte antigen 4 (CTLA4/CD152) is the most critical player in the negative and homeostatic regulation of T cell proliferation and activation. Intriguingly, we have reported that CTLA4 is expressed at low levels in primary human melanocytes, but not keratinocytes or other normal cell types, which raises the question regarding the function of CTLA4 in melanocytes. We posit that CTLA4 expressed on the surface of melanocytic cells may directly inhibit both CTLs and APCs via interaction with the B7 ligands expressed on both these cell types, which would lead to melanocyte/melanoma cell-mediated CTL inactivation and anergy leading to immunoevasion. Such immunoprotective effect may be an important part of the homeostatic function of CTLA4 by shielding the melanocyte stem cells (MSCs) during the destructive (catagen) phase of the hair follicle cycle. It is tempting to speculate that CTLA4 may be important for the maintenance of the MSC “immune privilege” (IP) and its loss in MSCs may cause the collapse of IP, which would lead to autoimmune destruction and vitiligo. The overall goal of this project is to delineate a novel mechanism of immunoevasion and survival of the melanocyte stem cells in skin. The specific hypothesis is that CTLA4 expression in melanocyte stem cells in the hair follicle (HF) bulge region determines their survival and immune privilege, and that loss of CTLA4 expression causes loss of MSCs, which leads to vitiligo. Moreover, it is hypothesized that CTLA4 expressed on the melanocytic cells directly inhibits effector T cells and APCs by a B7-mediated reverse inhibitory signaling mechanism. The proposed hypotheses will be addressed in two specific aims. In the first aim, we will characterize CTLA4 as a guardian of the melanocyte stem cell immune privilege in skin. In the second aim, the mechanism of the immunoinhibitory function of CTLA4 expressed by melanocyte stem cells will be delineated.

项目摘要 白癜风是最常见的皮肤色素脱失疾病，影响全球65-95万人。的 疾病的特征在于表皮黑色素细胞的选择性损失，导致皮肤色素沉着的损失， 可以局限于小区域或广泛传播的斑块。这种疾病不仅会导致毁容， 也影响患者的自尊和生活质量方面的心理健康。目前的战略 对于白癜风的治疗，最多只能是适度有效，不持久， 很麻烦白癜风是一种复杂的疾病，免疫系统之间存在复杂的相互作用， 系统、遗传倾向和环境因素。白癜风的症状有哪些？ 一种自身免疫性疾病，其中CD 8 + T细胞（也称为细胞毒性T淋巴细胞或CTL）起关键作用 导致黑素细胞破坏的效应子作用。必须严格控制这些皮肤常驻T细胞，以免 它们会在无意中被激活而产生自动反应这种控制是通过调节性T细胞来实现的 （TCLs），其抑制CTL应答。然而，目前尚不清楚黑素细胞和/或 黑素细胞干细胞本身在保护自身免受可能的CTL攻击方面起着积极的作用 通过固有的自身免疫保护机制。在这里，我们首次提出了这样一种新的机制。 细胞毒性T淋巴细胞抗原4（CTLA 4/CD 152）是负性和稳态免疫中最关键的参与者。 调节T细胞增殖和活化。有趣的是，我们已经报道了CTLA 4在低水平表达， 在原代人类黑素细胞中，而不是角质形成细胞或其他正常细胞类型中， 关于CTLA 4在黑素细胞中的功能的问题。我们证实CTLA 4表达于细胞表面， 黑素细胞可以通过与表达在黑素细胞表面的B7配体相互作用，直接抑制CTL和APC。 这两种细胞类型，这将导致黑素细胞/黑素瘤细胞介导的CTL失活和无反应性 导致免疫逃避。这种免疫保护作用可能是机体内环境稳定功能的重要组成部分 通过在毛发的破坏性（退化期）阶段屏蔽黑素细胞干细胞（MSC）来抑制CTLA 4的表达。 卵泡周期很容易推测CTLA 4可能对MSC的维持很重要， “免疫赦免”（immune privilege，IP）及其在骨髓间充质干细胞中的缺失可能导致IP的崩溃，从而导致自身免疫性疾病 破坏和白癜风。这个项目的总体目标是描述一种新的免疫逃避机制 和皮肤中黑素细胞干细胞的存活。具体的假设是，CTLA 4表达在 毛囊（HF）隆起区域中的黑素细胞干细胞决定它们的存活和免疫豁免， CTLA 4表达的缺失导致MSC的缺失，这导致白癜风。此外，据推测， 黑素细胞上表达的CTLA 4通过B7介导的逆转录酶抑制剂直接抑制效应T细胞和APC。 抑制性信号传导机制所提出的假设将在两个具体目标中得到解决。上 目的，我们将CTLA 4表征为皮肤中黑素细胞干细胞免疫豁免的监护人。在 第二个目的，探讨黑素干细胞表达CTLA 4的免疫抑制作用机制 将被划定。