Balance of chemokine entry and exit signals controls T cell accumulation in skin

趋化因子进入和退出信号的平衡控制皮肤中 T 细胞的积累

• 批准号: 7590369
• 负责人: SHANNON K BROMLEY
• 金额: $ 12.85万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-12 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590369
• 关键词: Adjuvant; Antigens; Atopic Dermatitis; Blood; Blood Circulation; CC chemokine receptor 4; CCR5 gene; CXCR3 gene; Cells; Cutaneous; Data; Delayed Hypersensitivity; Development; Doctor of Philosophy; Environment; Equilibrium; GPR2 gene; General Hospitals; Goals; Immune; Immune response; Immune system; Immunity; Immunologic Surveillance; Individual; Inflammation; Inflammatory; Investigation; Label; Laboratories; Ligands; Lymph; Lymphatic; Lymphocyte; Massachusetts; Mediating; Mentored Research Scientist Development Award; Modeling; Molecular Profiling; Mus; Pathogenesis; Pattern; Peripheral; Principal Investigator; Reaction; Recruitment Activity; Regulation; Research; Role; Signal Transduction; Site; Skin; Surveys; T memory cell; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Techniques; Tissues; cell motility; chemokine; chemokine receptor; experience; improved; in vivo; in vivo Model; intradermal injection; lymph nodes; migration; mouse model; novel; overexpression; pathogen; receptor expression; trafficking

With the proposed Research Scientist Development Award, the applicant will build upon her prior experience in antigen and chemokine regulation of T cell migration and immunity to study T cell recirculation using in vivo models of skin inflammation. The laboratory of Andrew D. Luster, MD, PhD, at Massachusetts General Hospital will provide a stimulating environment to further the candidate's scientific development toward achieving her ultimate goal of independent investigation. The proposed study will provide the applicant with the opportunity to examine the interplay of chemokines in regulating the migratory fate of T cells in inflamed skin. Both T cell entry into tissues from the bloodstream and T cell exit from tissues into afferent lymph control the accumulation of lymphocytes at peripheral sites and their participation in immune/inflammatory reactions. The roles of several individual chemokines in directing the traffic of T cell entry and exit from the skin have been characterized. However, the interplay between different chemokine signals in controlling the transit of T cells through skin remains completely unknown. Here, we hypothesize that a balance in chemokine entry, retention, and exit signals regulates the accumulation of effector/memory T cells within skin. In these proposed studies, we will use delayed type hypersensitivity and allergic dermatitis models to 1) Investigate the mechanisms that regulate the accumulation of effector/memory T cells in inflamed skin. We will track the migration of responding T cells by labelling cutaneous T cells in vivo with CFSE and determine the chemokine receptor expression profiles of CFSE+ T cells that remain in the skin, versus those that continue to migrate through the skin to draining lymph nodes; 2) Determine the consequence of effector/memory T cell antigen recognition in peripheral tissues on their expression of chemokine receptors and their retention in skin versus migration into afferent lymph; 3) Attempt to override the balance in chemokine receptor responsiveness using genetically altered T cells and mice that either lack or overexpress chemokine receptors or chemokine ligands. Results from these studies should further elucidate the mechanisms that regulate T cell transit through tissues and might benefit the treatment of pathological conditions in which large T cell infiltrates accumulate inappropriately in peripheral tissues.

通过拟议的研究科学家发展奖，申请人将在她之前的基础上再接再厉 具有抗原和趋化因子调节T细胞迁移和免疫研究T细胞的经验 使用皮肤炎症体内模型进行再循环。 Andrew D. Luster 医学博士、哲学博士的实验室，位于 马萨诸塞州总医院将提供一个激励性的环境，以促进候选人的科学发展 为实现独立调查的最终目标而发展。拟议的研究将 为申请人提供机会检查趋化因子在调节中的相互作用 发炎皮肤中 T 细胞的迁移命运。 T 细胞从血流进入组织和 T 细胞从组织退出进入传入淋巴管 淋巴细胞在外周部位的积累及其参与免疫/炎症 反应。几种趋化因子在指导 T 细胞进出细胞的交通中的作用 皮肤已被表征。然而，不同趋化因子信号之间的相互作用在控制 T 细胞穿过皮肤的过程仍然完全未知。在这里，我们假设平衡 趋化因子进入、保留和退出信号调节效应/记忆 T 细胞的积累 皮肤。在这些拟议的研究中，我们将使用迟发型超敏反应和过敏性皮炎模型来 1) 研究调节发炎皮肤中效应/记忆 T 细胞积累的机制。 我们将通过用 CFSE 标记体内皮肤 T 细胞来跟踪响应 T 细胞的迁移， 确定保留在皮肤中的 CFSE+ T 细胞的趋化因子受体表达谱，与 那些继续通过皮肤迁移到引流淋巴结的； 2) 确定后果 外周组织中效应/记忆 T 细胞抗原识别对其趋化因子受体表达的影响 以及它们在皮肤中的保留与迁移到传入淋巴中的比较； 3）尝试覆盖余额 使用基因改变的 T 细胞和缺乏或缺乏的小鼠进行趋化因子受体反应 过度表达趋化因子受体或趋化因子配体。这些研究的结果应该进一步 阐明调节 T 细胞穿过组织的机制，可能有利于治疗 大量 T 细胞浸润在外周组织中不适当地积聚的病理状况。