Integrin regulation of memory CD8 T cells

记忆 CD8 T 细胞的整合素调节

基本信息

批准号：
9215636
负责人：
YOJI SHIMIZU
金额：
$ 22.89万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-08 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9215636
关键词：
Adaptive Immune System Adhesions Adoptive Transfer Antigens Autoimmune Process Autoimmunity Binding Biological Preservation Blocking Antibodies Body Surface CD8-Positive T-Lymphocytes CD8B1 gene Cell Communication Cell Lineage Cell physiology Cells Cellular biology Clonal Expansion Collagen Connective Tissue Contracts Coupled Cues Cytokine Signaling Development Disease Drug or chemical Tissue Distribution Environment Epithelial Event Extracellular Matrix Flow Cytometry Generations Human Immune response Immune system Immunofluorescence Microscopy Immunologic Memory Infection Infection Control Inflammation Inflammatory Influenza Integrin Binding Integrin Inhibition Integrins Lead Ligands Longevity Lung Maintenance Mediating Memory Mesenchymal Microscopy Mus Phase Phenotype Play Population Positioning Attribute Primary Infection Process Regulation Residencies Role Sentinel Signal Transduction Site Smooth Muscle Myocytes Structure of parenchyma of lung Surface Surveys T memory cell T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Tissues Transforming Growth Factors Transgenic Organisms Vaccination Vaccines Vertebrates Viral Virus Diseases Wild Type Mouse adhesion receptor base cell motility improved in vivo insight integrin alpha1beta1 killings migration novel pathogen pathogen exposure peripheral blood public health relevance receptor receptor expression respiratory response therapy design treatment strategy two-photon vaccination strategy

项目摘要

DESCRIPTION (provided by applicant): In response to infection, CD8 T cells are activated by inflammation and foreign antigen and expand exponentially in number, develop effector functions that enable pathogen clearance, and then contract to form immunological memory. A subset of memory CD8 T cells, designated tissue-resident CD8 T cells (TRM), reside permanently in non-lymphoid tissue and provide critical protection at barrier sites in the event of reinfection. The fundamental processes that control the emergence of TRM are not fully understood. We propose that expression of receptors that mediate T cell interactions with extracellular matrix microenvironments in nonlymphoid tissue plays a critical role in TRM differentiation. Since the collagen-binding integrin 11 has been identified on TRM, we examined the response of 1 integrin deficient T cells following viral challenge. While CD8 T cell expression of 11 integrin is not required for initial T cell activation signals that lea to effector function, loss of 11 enhanced the development of a long-lasting TRM phenotype in the lung parenchyma following influenza infection. Based on these findings, we hypothesize that T cell 11 integrin expression inhibits the formation of tissue resident memory CD8 T cells by limiting effector phase expansion and suppressing responsiveness to TRM differentiation cues in vivo. We will test this hypothesis by tracking antigen-specific immune responses in vivo utilizing state-of-the art flow cytometry, quantitative immunofluorescence microscopy, and two-photon microscopy to complete two Specific Aims. First, we will define the requirement for 11 integrin in generating TRM populations in non-lymphoid tissue. We will characterize alterations in the primary immune response of 1 integrin deficient T cells and evaluate changes in CD8 T cell expansion, contraction, memory formation, and tissue distribution and residency using both local and systemic viral infections. Second, we will define the functional mechanism of 11 integrin inhibition of TRM formation by determining the role of 11 in regulating the response of effector T cells to TGF, and the adhesion and motility of TRM in non-lymphoid tissue. This project will lead to important advances in our understanding of TRM by characterizing a novel function for 11 integrin on T cells and defining a mechanism for generating increased populations of TRM in non-lymphoid tissue. These findings will aid in improving the generation of TRM following vaccination and treatment strategies for autoimmunity and inflammatory diseases.

描述（由适用提供）：针对感染，CD8 T细胞被注射和外抗原激活，并在数量上呈指数膨胀，开发人员效应子功能可以使病原体清除，然后收缩以形成免疫学记忆。记忆CD8 T细胞的子集，指定的组织居住的CD8 T细胞（TRM），永久存在于非淋巴组织中，并在屏障部位提供关键保护。重新感染。控制TRM出现的基本过程尚未完全理解。我们提出，在非淋巴组织中与细胞外基质微环境相互作用的接收器的表达在TRM分化中起关键作用。由于在TRM上已经鉴定出胶原结合素11，因此我们检查了病毒攻击后1整联蛋白缺乏的T细胞的响应。虽然对于效应子功能的初始T细胞激活信号并不需要CD8 T细胞的表达，但11的损失增强了影响力感染后肺实质中长期持久的TRM表型的发展。根据这些发现，我们假设T细胞11整合素表达抑制组织居民记忆记忆CD8 T细胞的形成限制效应子阶段的扩展和抑制体内TRM分化线索的响应能力。我们将使用最先进的流式细胞仪，定量免疫荧光显微镜和两光子显微镜在体内跟踪抗原特异性免疫回报来检验该假设，以完成两个特定的目标。首先，我们将定义对非淋巴组织中TRM群体产生TRM群体的需求。我们将表征1整联蛋白缺乏T细胞的一级免疫响应的改变，并评估CD8 T细胞扩张，收缩，记忆形成以及使用局部和全身病毒感染的组织分布和反应的变化。其次，我们将通过确定11的功能机理来定义11整联蛋白对TRM形成的抑制，通过确定11在减轻效应T细胞对TGF的响应中的作用以及TRM在非淋巴组织中的粘合和运动性。该项目将通过表征在T细胞上的11整合素的新功能并定义一种在非淋巴组织中产生TRM种群增加的机制，从而导致我们对TRM的重要进展。这些发现将有助于改善自身免疫性和炎症性疾病的疫苗和治疗策略后的TRM产生。