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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：
8960981
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/8960981
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 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 public health relevance 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.