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

将皮肤源性抗原加载到体内树突状细胞上以实现体外 T 反应

• 批准号: 7707028
• 负责人: James J. Campbell
• 金额: $ 7.88万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-12 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7707028
• 关键词: 3-Dimensional; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Biological Assay; Biological Process; Blood; CC chemokine receptor 4; CCR9 gene; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Separation; Cell surface; Cells; Coculture Techniques; Cutaneous; Data; Dendritic Cells; Dermis; Development; Disease; Dose; E-Selectin; Epidermis; Event; Exposure to; Histocompatibility Testing; Home environment; Homing; Human; Immune; Immune System Diseases; Immune system; Immunization; Immunologic Memory; Immunologic Monitoring; In Vitro; Integrins; Intestines; Knowledge; Ligands; Lymph; Lymphocyte; Lymphoid; Mammals; Memory; Methods; Modeling; Molecular; Organ; Organism; Peripheral; Population; Process; Production; Psoriasis; Reticular Cell; Series; Skin; Small Intestines; Stimulus; Surface; System; T-Lymphocyte; Testing; Time; Tissues; Treatment Protocols; Tropism; Vaccines; chemokine receptor; cytokine; design; experience; human disease; imprint; in vivo; insight; lymph nodes; novel; novel strategies; prevent; programs; public health relevance; response; tissue tropism; trafficking; vaccination strategy

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.

描述（由申请方提供）：循环T淋巴细胞池包含具有不同组织嗜性的多种抗原经历亚群。最容易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监视其自身的靶组织。这种严格的“劳动分工”的进化目的仍然是有争议的。然而，我们对这一现象的理解，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策略。在设计有效的疫苗接种策略和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嗜性的概念。初始T细胞没有能力归巢到非淋巴器官，如皮肤。这种能力是在皮肤淋巴结内暴露于皮肤衍生抗原后获得的。当抗原呈递细胞（主要是树突状细胞）从发炎的皮肤中摄取抗原并展示在细胞表面MHC分子上时，就会发生这个过程。幼稚T细胞响应抗原而发生的大多数变化（如克隆增殖、幼稚标志物的丢失和激活/效应/记忆标志物的获得）可发生在任何给定的淋巴器官内。然而，E-选择素配体和趋化因子受体CCR 4（归巢到发炎皮肤所需的分子）的诱导对于皮肤淋巴结内的树突状细胞是独特的。有趣的是，我们的初步数据表明，只有一个子集的抗原反应性幼稚T细胞表达皮肤特异性归巢标志物内发炎的皮肤淋巴结。我们假设只有皮肤淋巴结内发现的树突状细胞的特定亚群可以诱导皮肤归巢分子的T细胞表达。我们提出1）设计用于在体内用来自发炎皮肤的抗原加载树突状细胞以在体外诱导幼稚T细胞分化成皮肤归巢细胞的模型;和2）使用该模型来确定皮肤淋巴结内的八个或更多个可识别的树突状细胞群体中的哪一个具有触发该皮肤特异性分化程序的能力。公共卫生关系：皮肤是保护生物体免受外界致病因子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该器官的细胞。了解免疫系统如何“记住”先前在皮肤中遇到的抗原是开发针对通过皮肤攻击的药剂的疫苗以及开发针对皮肤的免疫疾病（如牛皮癣）的治疗方法的重要考虑因素。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，以排斥致病因子。