Real-time Measurement of Self-antigen Recognition by Lymphocytes In Vivo

体内淋巴细胞自身抗原识别的实时测量

• 批准号: 8263743
• 负责人: Alex Yee-Chen Huang
• 金额: $ 23.55万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-13 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8263743
• 关键词: Address; Affect; Animals; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune Process; Autoimmunity; B-Lymphocytes; Behavior; Biological Assay; Biology; Bone Marrow; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Communication; Cell physiology; Cell surface; Cells; Chimera organism; Chronic; Communication; Complex; Data; Dendritic Cells; Development; Discrimination; Education; Elements; Environment; Event; Future; Goals; Hematopoietic; Imaging Device; Imaging technology; Immune; Immune response; Immune system; Immunity; Immunologic Surveillance; Immunologic Techniques; Immunology; Individual; Infection; Inflammatory; Investigation; Laboratories; Laser Scanning Microscopy; Lead; Life; Ligands; Lymphocyte; Lymphocyte Function; Lymphoid; Maintenance; Major Histocompatibility Complex; Malignant Neoplasms; Mature Lymphocyte; Mature T-Lymphocyte; Measurable; Measurement; Measures; Molecular; Mus; Occupations; Organ; Peptides; Peripheral; Photons; Play; Population; Process; Publishing; Regulatory T-Lymphocyte; Relative (related person); Research Personnel; Resistance; Resolution; Role; Scanning; Self Perception; Self Tolerance; Series; Shapes; Signal Transduction; Source; Staging; T cell response; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Time; Tissues; Vaccination; Vascular System; base; cell behavior; cell motility; cell type; chemokine; in vivo; insight; lymph nodes; migration; pathogen; public health relevance; research study; success; thymocyte; tumor

DESCRIPTION (provided by applicant): The job of our immune system is to recognize foreign invaders and to eliminate the threat while sparing self-tissues. Such discrimination occurs at the level of T cell receptor (TCR) recognition of peptide/MHC molecular complexes on target cell surfaces. Signals arising from recognition of self-peptide/MHC molecules (self-ligands) by developing thymocytes determine lineage commitment and selection of the TCR repertoire. However, the role of self-ligand interaction in peripheral mature T cells is controversial. Specifically, how the presence of self-ligands influences lymphocyte function and migratory behavior in vivo remains unclear. Until recently, such determination largely comes from indirect experimental evidence. With the aid of 2-photon laser scanning microscopy, however, investigators can now begin to understand intercellular dynamics within an intact tissue microenvironment such as the lymph node. An example of the utility of this powerful imaging tool is the uncovering of the role inflammatory chemokines play in the orchestration of multi-cellular cooperation during the intranodal induction of a primary immune response8. In the current study, we propose to provide direct, high-resolution data addressing the impact of self-ligand surveillance by circulating mature lymphocytes in the lymph nodes. We also plan to undertake a series of studies aimed to delineate the relative contribution of various self-ligand-expressing cells during immune surveillance by naive lymphocytes as well as other specialized cells such as regulatory T cells. This will be accomplished by utilizing the state-of-the-art 2-photon laser scanning microscopy available in our own laboratory, combined with classical immunological techniques and mouse bone marrow chimera manipulations. Success in this endeavor will provide new insights into how self-ligands contribute to the global lymphocyte behavior and function in vivo, and will set the stage for a detailed understanding of how self-peptide/MHC interactions shape the responses of the T cell populations against cognate antigens encountered during infection and vaccination. A detailed understanding of the intricate and complex cellular communication in the tissue microenvironment will allow future inquiries into the in vivo cellular mechanisms that lead to the development of dysregulated state of self-tolerance, such as autoimmunity, cancer and chronic infection. PUBLIC HEALTH RELEVANCE: Recognition of positive-selecting self-ligands plays a crucial role in developing T lymphocytes during thymic education. However, the role of such self-peptide antigen recognition in the periphery for mature T lymphocytes is controversial. The current study seeks to investigate the role self-peptide antigens play in the in vivo behavior of T lymphocytes in secondary lymphoid organs. We aim to provide high-resolution data addressing the impact of self-ligand interactions, and to seek the relative contribution of various stromal and immune cellular subsets in affecting the migratory behavior of naive and regulatory T lymphocytes in vivo. The proposed studies will set the stage for proper understanding of how self-peptide/MHC interactions shape the responses of these T cell populations against cognate antigens seen during infection and vaccination. Successful execution of this project will also provide new insights into potential mechanisms underlying the development of autoimmunity, induction of tumor tolerance and maintenance of homeostatic immune responses.

描述（由申请人提供）：我们的免疫系统的工作是识别外来入侵者并消除威胁，同时保护自身组织。这种区分发生在靶细胞表面的肽/MHC 分子复合物的 T 细胞受体 (TCR) 识别水平上。发育中的胸腺细胞识别自肽/MHC 分子（自配体）所产生的信号决定了 TCR 谱系的谱系定型和选择。然而，自身配体相互作用在外周成熟T细胞中的作用存在争议。具体而言，自身配体的存在如何影响体内淋巴细胞功能和迁移行为仍不清楚。直到最近，这种决定主要来自间接实验证据。然而，借助 2 光子激光扫描显微镜，研究人员现在可以开始了解完整组织微环境（例如淋巴结）内的细胞间动力学。这种强大的成像工具的实用性的一个例子是揭示炎症趋化因子在初次免疫反应的结内诱导过程中协调多细胞合作中所发挥的作用8。在当前的研究中，我们建议提供直接、高分辨率的数据，通过淋巴结中循环成熟淋巴细胞来解决自身配体监测的影响。我们还计划进行一系列研究，旨在描述各种自身配体表达细胞在幼稚淋巴细胞以及其他特殊细胞（例如调节性 T 细胞）的免疫监视过程中的相对贡献。这将通过利用我们自己实验室最先进的 2 光子激光扫描显微镜，结合经典免疫学技术和小鼠骨髓嵌合体操作来实现。这项工作的成功将为了解自配体如何促进体内整体淋巴细胞行为和功能提供新的见解，并为详细了解自肽/MHC相互作用如何影响T细胞群对淋巴细胞的反应奠定基础。感染和疫苗接种过程中遇到的同源抗原。对组织微环境中错综复杂的细胞通讯的详细了解将有助于未来研究导致自我耐受失调状态发展的体内细胞机制，例如自身免疫、癌症和慢性感染。 公共卫生相关性：在胸腺教育过程中，阳性选择自身配体的识别在 T 淋巴细胞的发育中起着至关重要的作用。然而，这种外周自肽抗原识别对于成熟T淋巴细胞的作用是有争议的。本研究旨在探讨自肽抗原在次级淋巴器官中 T 淋巴细胞的体内行为中所发挥的作用。我们的目标是提供高分辨率数据来解决自身配体相互作用的影响，并寻求各种基质和免疫细胞亚群在影响体内幼稚和调节性 T 淋巴细胞迁移行为方面的相对贡献。拟议的研究将为正确理解自肽/MHC 相互作用如何塑造这些 T 细胞群针对感染和疫苗接种过程中出现的同源抗原的反应奠定基础。该项目的成功执行还将为自身免疫发展、肿瘤耐受诱导和稳态免疫反应维持的潜在机制提供新的见解。