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: 8191110
• 负责人: Alex Yee-Chen Huang
• 金额: $ 19.63万
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8191110
• 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; 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认识到外国入侵者并消除威胁，同时放弃自我组织。这种歧视发生在靶细胞表面上肽/MHC分子复合物的T细胞受体（TCR）识别水平上。通过识别自肽/MHC分子（自配体）而产生的信号通过开发胸腺细胞决定了TCR库的谱系承诺和选择。但是，自配体相互作用在周围成熟T细胞中的作用是有争议的。具体而言，自我配体的存在如何影响体内淋巴细胞功能和迁移行为尚不清楚。直到最近，这种确定很大程度上来自间接的实验证据。然而，借助2光子激光扫描显微镜，研究人员现在可以开始理解完整的组织微环境（例如淋巴结）内的细胞间动力学。这种强大的成像工具实用性的一个例子是揭示了炎症性趋化因子在原代免疫反应内诱导过程中多细胞合作的编排中所起的作用。在当前的研究中，我们建议提供直接的高分辨率数据，以解决通过淋巴结中成熟的淋巴细胞循环自我监测的影响。我们还计划进行一系列旨在描绘出幼稚淋巴细胞以及其他专业细胞（例如调节T细胞）在免疫监视过程中各种表达自我表达细胞的相对贡献的研究。这将通过利用我们自己的实验室中的最先进的2-Photon激光扫描显微镜，结合经典的免疫技术和小鼠骨髓嵌合体操纵来实现。在这项工作中的成功将提供新的见解，即自我配体如何对全球淋巴细胞行为和体内功能做出贡献，并为详细了解对在感染和疫苗感染过程中对cognate抗原遭受的抗原遇到的T细胞种群的反应的详细理解奠定了基础。对组织微环境中复杂且复杂的细胞通信的详细理解将使将来对体内细胞机制进行询问，这些机制导致自身免疫，癌症和慢性感染等自我耐受状态失调状态的发展。 公共卫生相关性：对积极选择的自我配体的认识在胸腺教育期间发展T淋巴细胞中起着至关重要的作用。然而，这种自肽抗原识别在成熟T淋巴细胞的外围的作用是有争议的。当前的研究旨在研究自肽抗原在二次淋巴机构中T淋巴细胞体内行为中的作用。我们旨在提供高分辨率数据，以解决自我相互作用的影响，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淋巴细胞的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相互作用如何影响这些T细胞种群对感染和疫苗接种过程中观察到的同源抗原的反应奠定阶段。该项目的成功执行还将为自身免疫发展，诱导肿瘤耐受性和维持体内稳态免疫反应的潜在机制提供新的见解。