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

项目概要 白癜风是最常见的皮肤色素脱失性疾病，影响全球 65-9500 万人。的 该疾病的特征是表皮黑素细胞选择性丧失，导致皮肤色素沉着丧失 斑块可以局限于小区域或广泛传播。这种病不仅会导致毁容 还影响患者在自尊和生活质量方面的心理健康。目前的策略 治疗白癜风的效果充其量只是中等，不持久，并且在实际和经济上 繁重的。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和贡献 系统、遗传倾向和环境因素。然而，白癜风从根本上来说是一种 CD8 T 细胞（也称为细胞毒性 T 淋巴细胞或 CTL）发挥关键作用的自身免疫性疾病 导致黑素细胞破坏的效应器作用。必须严格控制这些皮肤驻留 T 细胞，以免 它们会无意中被激活而产生自动反应。这种控制是通过调节性 T 细胞实现的 （Tregs），抑制 CTL 反应。然而，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 攻击方面发挥着积极作用 通过固有的自我免疫保护机制。在这里，我们首次提出这样一种新颖的机制。 细胞毒性 T 淋巴细胞抗原 4 (CTLA4/CD152) 是阴性和稳态中最关键的参与者 T 细胞增殖和激活的调节。有趣的是，我们报道了 CTLA4 的低表达 原代人黑素细胞中的水平，但不包括角质形成细胞或其他正常细胞类型，这会提高 关于 CTLA4 在黑素细胞中的功能的问题。我们假设 CTLA4 表达于 黑素细胞可以通过与表达于黑色素细胞上的 B7 配体相互作用，直接抑制 CTL 和 APC。 这两种细胞类型，都会导致黑色素细胞/黑色素瘤细胞介导的 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体内平衡功能的重要组成部分 CTLA4 通过在头发破坏（退行期）阶段屏蔽黑素细胞干细胞 (MSC) 来发挥作用 卵泡周期。人们很容易推测 CTLA4 可能对于 MSC 的维持很重要 “免疫特权”（IP）及其在MSCs中的丧失可能导致IP崩溃，从而导致自身免疫 破坏和白癜风。该项目的总体目标是描绘一种新的免疫逃避机制 以及皮肤中黑素细胞干细胞的存活。具体假设是 CTLA4 表达于 毛囊 (HF) 隆起区域的黑色素细胞干细胞决定其生存和免疫特权，并且 CTLA4 表达缺失会导致 MSC 缺失，从而导致白癜风。此外，假设 黑素细胞上表达的 CTLA4 通过 B7 介导的逆转直接抑制效应 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。在第一个 目标，我们将 CTLA4 描述为皮肤黑素细胞干细胞免疫特权的守护者。在 第二个目的，黑素细胞干细胞表达的CTLA4的免疫抑制功能机制 将被划定。

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.