Dendritic Cell Control of Skin Immunity

树突状细胞控制皮肤免疫

• 批准号: 8195859
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195859
• 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）： 传染病疫苗接种是预防退伍军人和现役士兵发病和死亡的主要工具。与对感染的免疫反应类似，有效的疫苗接种需要表达 MHC II 类肽复合物的专业抗原呈递细胞激活 CD4+ 辅助 T 细胞。大多数疫苗接种是通过皮下注射进行的；因此，了解皮肤中 MHC II 类依赖性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，我们发现皮下免疫后 CD4+ T 细胞的克隆选择和扩增需要淋巴驻留和迁移 DC 的抗原加工和呈递。淋巴驻留 DC 的早期抗原呈递启动了引流 LN 中抗原特异性 T 细胞的激活和捕获，而不诱导克隆扩增。然而，迁移性 DC 与保留在 LN 中的 CD4+ T 细胞相互作用以诱导增殖。因此，不同的 DC 子集相互协作来警告和捕获适当的细胞，然后许可其扩张和分化。这些初步结果引出了一个显而易见的问题：为什么需要两个 DC 群体来启动 CD4+ T 细胞？在当前的提案中，我们将剖析细胞和分子机制，这些机制是对皮肤中传递的抗原做出反应时需要两种不同的树突细胞群的基础。我们有三个具体目标。在我们的第一个目标中，我们将利用大的抗原缀合微球来限制抗原呈递给一组 DC。这将检验以下假设：仅限于迁移 DC 的抗原呈递不能启动幼稚 CD4+ T 细胞。在我们的后两个目标中，我们将研究对淋巴驻留和迁移 DC 的要求的两种替代解释。首先，免疫荧光和分子技术将用于剖析 T 细胞与淋巴驻留 DC 相互作用后的定位。我们将考虑这样的假设：LN 中的幼稚 T 细胞必须改变位置以允许与负载抗原的迁移 DC 相互作用。最后，我们将确定 CD4+ T 细胞在淋巴驻留 DC 启动后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 群体调节的两个不同步骤中？了解 CD4+ T 细胞激活的要求将指导开发更有效的疫苗接种，以对抗导致士兵和退伍军人严重疾病的病原体。 公共卫生相关性： 疫苗接种一直是预防士兵在训练和战争期间发病和死亡的主要机制。然而，退伍军人及其医生仍然担心单独接种疫苗（例如炭疽疫苗）或联合接种疫苗的有效性和长期安全性。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 细胞是一种协调免疫反应的白细胞。许多疫苗是通过注射到皮肤中来输送的。在当前的提案中，我们表明两种不同类型的白细胞协同诱导 CD4+ T 细胞对注射到皮肤中的蛋白质做出反应。我们将探索使这一复杂途径成为必要的生物学机制。建立更好的皮肤 T 细胞激活范例应该可以指导改进疫苗的开发，并改善士兵和退伍军人的健康。