Dendritic Cell Control of Skin Immunity

树突状细胞控制皮肤免疫

• 批准号: 7689602
• 负责人: TERRI M. LAUFER
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7689602
• 关键词: Anatomy; Anthrax disease; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Behavior; Biochemical; Bone Marrow; CD4 Positive T Lymphocytes; Cells; Chimera organism; Clonal Expansion; Communicable Diseases; Complex; Data; Dendritic Cells; Development; Disease; Event; Exclusion; Health; Helper-Inducer T-Lymphocyte; Immune response; Immunity; Immunization; Immunofluorescence Immunologic; Infection; Injection of therapeutic agent; Lead; Leukocytes; Licensing; Location; Lymphatic; Lymphoid; MHC Class II Genes; Mediating; Microspheres; Modeling; Molecular; Morbidity - disease rate; Pathway interactions; Peptide/MHC Complex; Peptides; Physicians; Population; Positioning Attribute; Prevention; Proteins; Regulation; Relative (related person); Safety; Signal Transduction; Skin; Soldier; T cell response; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Tissues; Training; Transgenic Mice; Travel; Vaccination; Vaccine Design; Vaccines; Veterans; War; base; chemokine; chemokine receptor; cytokine; improved; lymph nodes; mortality; pathogen; prevent; public health relevance; receptor expression; response; subcutaneous; tool

DESCRIPTION (provided by applicant): Vaccination against infectious diseases is a major tool for prevention of morbidity and mortality for both veterans and active-duty soldiers. Effective vaccination, similar to the immune response to infection, requires activation of CD4+ helper T cells by professional antigen presenting cells expressing MHC class II-peptide complexes. Most vaccinations are delivered subcutaneously; thus, understanding the regulation of MHC class II- dependent immune responses in the skin will inform the rational design of vaccines. Surprisingly, we found that antigen processing and presentation by both lymphoid- resident and migratory DCs was required for clonal selection and expansion of CD4+ T cells following subcutaneous immunization. Early antigen presentation by lymphoid- resident DCs initiated activation and trapping of antigen-specific T cells in the draining LN, without inducing clonal expansion. Migratory DCs, however, interact with the CD4+ T cells retained in the LN to induce proliferation. Therefore, distinct DC subsets cooperate to alert and trap the appropriate cell and then license its expansion and differentiation. These preliminary results lead to the obvious question: why are two DC populations necessary to prime CD4+ T cells? In the current proposal, we will dissect the cellular and molecular mechanisms that underlie the requirement for two distinct populations of dendritic cells in the response to antigens delivered in the skin. We have three Specific Aims. In our first Aim, we will utilize large antigen-conjugated microspheres to limit antigen presentation to one population of DCs. This will test the hypothesis that antigen presentation restricted to migratory DCs cannot prime naove CD4+ T cells. In our second two Aims, we will examine two alternative explanations for the requirement for both lymphoid-resident and migratory DCs. First, immunofluorescence and molecular techniques will be utilized to dissect the localization of T cells following interaction with lymphoid-resident DCs. We will consider the hypothesis that naove T cells in the LN must change location to permit interaction with antigen-loaded migratory DCs. Finally, we will determine the biochemical setpoint and behavior of CD4+ T cells following priming by lymphoid-resident DCs. Does T cell activation occur in two distinct steps regulated by two different DC populations? Understanding the requirements for activation of CD4+ T cells will guide the development of more effective vaccinations against pathogens that cause significant disease in soldiers and veterans. PUBLIC HEALTH RELEVANCE: Vaccination has been a major mechanism for prevention of soldier morbidity and mortality during training and war. Yet, veterans and their physicians remain concerned about the efficacy and longterm safety of vaccinations delivered either individually, such as anthrax vaccination, or in combination to soldiers. The immune response to both pathogens and vaccinations rely on activation of CD4+ T cells, a white blood cell that orchestrates the immune response. Many vaccines are delivered by injection into the skin. In the current proposal, we show that two different types of white blood cells collaborate to induce CD4+ T cell responses to proteins injected into the skin. We will explore the biologic mechanisms that make this complex pathway necessary. Establishing a better paradigm for the activation of T cells in the skin should guide the development of improved vaccines and improve the health of both soldiers and veterans.

描述（由申请人提供）： 针对传染病的疫苗接种是预防退伍军人和现役士兵的发病率和死亡率的主要工具。有效的疫苗接种，类似于对感染的免疫反应，需要通过表达MHC II类肽复合物的专业抗原呈递细胞来激活CD4+辅助T细胞。大多数疫苗接种是皮下进行的；因此，了解皮肤中MHC II类免疫反应的调节将为疫苗的合理设计提供信息。令人惊讶的是，我们发现淋巴样和迁移DC的抗原加工和表现是在皮下免疫后CD4+ T细胞扩展的克隆选择和膨胀所必需的。淋巴样DC的早期抗原表现出来，引发了抗原特异性T细胞在排水LN中的激活和捕获，而无需诱导克隆膨胀。然而，迁移DC与保留在LN中的CD4+ T细胞相互作用以诱导增殖。因此，独特的DC子集配合以提醒和捕获适当的单元，然后许可其扩展和差异化。这些初步结果导致了一个明显的问题：为什么需要两个DC群体来启用CD4+ T细胞？在当前的提案中，我们将剖析细胞和分子机制，这些机制是对在皮肤中递送的抗原反应中对两种不同的树突状细胞种群的要求。我们有三个具体的目标。在我们的第一个目标中，我们将利用大型抗原偶联的微球将抗原呈现限制为一个DC人群。这将检验以下假设：抗原表现仅限于迁移的DC不能使NAOVE CD4+ T细胞构成基础。在我们的第二个目标中，我们将研究两个替代解释，以供淋巴样居民和迁移DC。首先，将利用免疫荧光和分子技术来剖析与淋巴样居民DC相互作用后T细胞的定位。我们将考虑以下假设：LN中的NAOVE T细胞必须更改位置以允许与抗原负载的迁移DC相互作用。最后，我们将确定通过淋巴样居民DC启动CD4+ T细胞的生化设定点和行为。 T细胞激活是否发生在两个不同的DC种群调节的两个不同的步骤中？了解激活CD4+ T细胞的要求将指导开发针对士兵和退伍军人引起严重疾病的病原体的更有效的疫苗接种。 公共卫生相关性： 疫苗接种一直是预防训练和战争期间士兵发病率和死亡率的主要机制。然而，退伍军人及其医生仍然关心单独接种的疫苗接种的功效和长期安全性，例如炭疽疫苗接种或士兵联合使用。对病原体和疫苗接种的免疫反应依赖于CD4+ T细胞的激活，CD4+ T细胞是一种策划免疫反应的白细胞。许多疫苗是通过注射到皮肤中的。在当前的建议中，我们表明两种不同类型的白细胞合作，诱导注入皮肤中注入的蛋白质的CD4+ T细胞反应。我们将探索使这一复杂途径必要的生物学机制。建立更好的范式来激活皮肤中T细胞的激活，应指导改善疫苗的发展并改善士兵和退伍军人的健康。