Lymph Node Structure and Function in Tolerance: Role of Laminins

耐受性中的淋巴结结构和功能：层粘连蛋白的作用

基本信息

批准号：
9056643
负责人：
Jonathan S Bromberg
金额：
$ 38.38万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-20 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9056643
关键词：
Adoptive Transfer Alloantigen Antibodies Antigens Apoptosis Apoptotic Area Autoimmunity Biochemical Genetics Blood Blood Vessels Bone Marrow Transplantation Cell Communication Cell physiology Cells Cellular Structures Data Dendritic Cells Development Endothelial Cells Environment Fiber Gatekeeping Gene Expression Profile Generations Goals Graft Rejection Health High Endothelial Venule Immune Immune response Immunity Immunization Immunologics Immunology Infection Integrins Investigation Laboratories Laminin Lead Lymph Node Cortex Lymphatic Lymphocyte Lymphoid Methods Microscopy Modeling Molecular Morphology Movement Organ Pathway interactions Positioning Attribute Process Publications Regulatory T-Lymphocyte Research Resistance Reticular Cell Role Selectins Signal Transduction Site Spleen Stromal Cells Structure T memory cell T-Lymphocyte Techniques Testing Transplantation Transplantation Immunology Transplantation Tolerance Tumor Immunity Vaccination Viral Tumor Antigens anergy cell motility chemokine clinically relevant cohort fiber cell in vivo islet laminin-5 lymph nodes migration novel novel therapeutic intervention prevent response small molecule trafficking two-photon

项目摘要

DESCRIPTION (provided by applicant): Achieving tolerance remains the most important goal in transplantation immunology. Models of tolerance employing co-stimulatory blockade are among the most robust and clinically relevant approaches. Much is known about the mechanisms of tolerance that are operative during co-stimulatory blockade, such as energy, apoptosis, and regulatory T cells (Treg). However, it is often difficult to induce and maintain robust tolerance that is resistant to external perturbations. This suggests that other important immunologic mechanisms that determine tolerance remain to be elucidated. Our laboratory has focused on the role of migration, trafficking and secondary lymphoid organ structure as crucial regulatory processes that determine whether immune interactions result in immunity versus tolerance. In several key publications we demonstrated that tolerance is initiated in lymph nodes (LN) through the precise interaction of specific alloantigen presenting cells with naïve antigen specific T cells to generate regulatory suppressive T cells. This interaction occurs in the LN, and is dependent on the intricate coordination of many molecular signals. Subsequent trafficking of the suppressive T cells is critical, so that migration from blood to grafts and then into lymphatic has distinct and unique suppressive effects, in comparison to migration through blood and LNs. We have elucidated several novel and unexpected mechanisms that are required for tolerance induction, and these mechanisms relate to the interaction of LN structure with the cellular and molecular mechanisms of lymphocyte responses. The results demonstrate that T cells destined to become suppressors are found in only one region of the LN, called the cortical ridge. In contrast, T cells destined to become effectors are found scattered throughout the LN. The cortical ridge is particularly rich in specialized fibers and stromal cells, called fibroblastic reicular cells (FRC), suggesting a unique function or arrangement for these cells and their associated fibers. Together these observations lead to the hypothesis that the LN domain of the cortical ridge, that encompasses the HEV and their surrounding stromal fibers, is a major locus for tolerization. During tolerization naïve T cells and alloantigen presenting pDC enter this domain and remain around the HEV within the stromal fibers. Precise stromal cell function and fiber arrangement are required to create and maintain the microenvironment necessary for Treg induction. These Treg persist in this high-traffic region and act as gatekeepers for new T cells that traverse the HEV. These Treg regulate the migration, activation, and fate of new naïve antigen specific T cells as they enter the LN, and thus the Treg determine tolerance or immunity.

描述（由应用程序提供）：实现耐受性仍然是移植免疫学中最重要的目标。采用共刺激性阻滞的容忍模型是最强大和临床相关的方法之一。关于在共刺激性阻滞中运行的耐受性机制，例如能量，凋亡和调节性T细胞（TREG）。但是，通常很难诱导和保持对外部扰动具有抗性的耐受性。这表明确定公差的其他重要免疫机制尚待阐明。我们的实验室专注于移民，贩运和次级淋巴器官结构的作用，这是确定免疫相互作用是否导致免疫学和耐受性的关键调节过程。在几个关键出版物中，我们证明了通过特定的同种抗原细胞与幼稚的抗原特异性T细胞的精确相互作用在淋巴结（LN）中启动耐受性，以产生调节性抑制性T细胞。这种相互作用发生在LN，并且取决于许多分子信号的复杂协调。随后对抑制性T细胞的运输至关重要，因此与通过血液和LN的迁移相比，从血液到移植物再迁移到淋巴管中具有独特而独特的抑制作用。我们阐明了耐受性诱导所需的几种新颖和意外的机制，以及与LN结构与淋巴细胞反应的细胞和分子机制相互作用有关的这些机制。结果表明，只有在LN的一个区域，称为皮质脊的T细胞。相比之下，发现注定要成为生效子的T细胞散布在整个LN中。皮质脊特别富含专门的纤维和基质细胞，称为成纤维细胞胶状细胞（FRC），这表明这些细胞及其相关纤维具有独特的功能或排列。这些观察结果一起导致了一个假设，即皮质脊的LN结构域增强了HEV及其周围的基质纤维，是耐受性的主要基因座。在耐受性的过程中，幼稚的T细胞和同种抗原呈现PDC进入该结构域，并在基质纤维中留在HEV周围。需要精确的基质细胞功能和纤维排列来创建和维持Treg诱导所需的微环境。这些Treg持续存在在这个高流量区域，并充当横穿HEV的新T细胞的守门人。这些Treg调节了新的幼稚抗原特异性T细胞进入LN时的迁移，激活和命运，因此Treg确定了公差或免疫力。