Loading Skin-Derived Antigen on Dendritic Cells in Vivo for T Responses in Vitro

描述(由申请人提供)：循环T淋巴细胞池包含多个抗原经验亚群，具有不同的组织取向。最被理解的两种类型是与皮肤或肠道相关的类型。每个亚群负责免疫记忆和对其自身目标组织的监视。这种严格的“分工”的进化目的仍然存在争议。然而，我们对这一现象的理解的提高，特别是在分子水平上的理解，无疑将激发治疗和预防人类疾病的新战略。在设计有效的疫苗接种策略时，以及在开发治疗器官特异性自身免疫性疾病的新方法时，必须考虑组织特异性淋巴细胞趋向性的概念。幼稚T细胞不具有归宿到皮肤等非淋巴器官的能力。这种能力是在暴露于皮肤淋巴结内的皮源性抗原后获得的。当抗原提呈细胞(主要是树突状细胞)从发炎的皮肤中提取抗原并显示在细胞表面的MHC分子上时，这一过程就会发生。原始T细胞对抗原的反应发生的大多数变化(如克隆性增殖、原始标记的丢失和激活/效应/记忆标记的获得)可以发生在任何给定的淋巴器官中。然而，E-选择素配体和趋化因子受体CCR4(归巢到发炎皮肤所需的分子)的诱导是皮肤淋巴结内的树突状细胞所独有的。有趣的是，我们的初步数据表明，在发炎的皮肤淋巴结内，只有一小部分抗原反应性的幼稚T细胞表达皮肤特异性归巢标记。我们假设，只有在皮肤淋巴结内发现的特定亚群的树突状细胞才能诱导皮肤归巢分子的T细胞表达。我们建议1)设计一种在体内用炎症皮肤抗原负载树突状细胞的模型，以在体外诱导原始T细胞向皮肤归巢细胞分化；2)使用该模型来确定皮肤结节内可识别的8种或更多树突状细胞中的哪一种具有触发这种皮肤特异性分化程序的能力。与公共健康相关：皮肤是保护有机体免受外界致病因素影响的主要物理屏障之一，人类和其他哺乳动物的免疫系统包含一组专门用于巡逻这个器官的细胞。了解免疫系统如何“记住”以前在皮肤中遇到的抗原，是为通过皮肤攻击的制剂开发疫苗，以及开发针对皮肤的免疫疾病(如牛皮癣)的治疗方法时的一个重要考虑因素。我们的项目将帮助我们了解免疫细胞如何发展进入皮肤的能力，以击退致病因子。

DESCRIPTION (provided by applicant): The circulating T lymphocyte pool contains multiple antigen-experienced subpopulations bearing distinct tissue tropisms. The two best understood types are those associated with the skin or the intestine. Each subset is responsible for immunological memory and surveillance of its own target tissue. The evolutionary purpose for this strict "division of labor" remains debatable. However, an improvement in our understanding of this phenomenon, particularly at the molecular level, will undoubtedly inspire new strategies to treat and prevent human disease. The concept of tissue-specific lymphocyte tropism must be considered when designing efficient vaccination strategies, and when developing new approaches to treat organ-specific autoimmune disorders. Naive T cells do not have the ability to home to non-lymphoid organs such as skin. This ability is gained after exposure to skin-derived antigen within cutaneous lymph nodes. This process occurs when antigen-presenting cells (primarily dendritic cells) take up antigen from inflamed skin for display on cell-surface MHC molecules. Most changes that occur to naive T cells in response to antigen (such as clonal proliferation, loss of naive markers, and gain of activation/effector/memory markers) can occur within any given lymphoid organ. However, induction of the E-selectin ligand and the chemokine receptor CCR4 (molecules required for homing to inflamed skin) is unique to the dendritic cells within cutaneous lymph nodes. Interestingly, our preliminary data suggests that only a subset of antigen-responsive naive T cells express skin-specific homing markers within inflamed cutaneous lymph nodes. We hypothesize that only a specific subpopulation of dendritic cells found within cutaneous lymph nodes can induce T cell expression of skin homing molecules. We propose 1) to design a model for loading dendritic cells with antigen from inflamed skin in vivo to induce differentiation of naive T cells into skin- homing cells in vitro; and 2) to use this model to determine which of the eight or more identifiable dendritic cell populations within cutaneous nodes have the ability to trigger this skin-specific differentiation program. PUBLIC HEALTH RELEVANCE: The skin is one of the major physical barriers protecting an organism from disease- causing agents in the outside world, and the immune systems of humans and other mammals contain a specialized set of cells dedicated to patrolling this organ. Understanding how the immune system "remembers" antigens that have been previously encountered in the skin is an important consideration in developing vaccines for agents that attack through the skin, and in developing treatments for immune diseases that target the skin, such as psoriasis. Our project will help us to understand how immune cells develop the ability to enter the skin to repulse disease-causing agents.