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

• 批准号: 10046835
• 负责人: Jonathan S Bromberg
• 金额: $ 46.35万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-20 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10046835
• 关键词: Adhesions; Alloantigen; Allografting; Antibodies; Apoptotic; Area; Autoimmunity; Binding; CD8-Positive T-Lymphocytes; Cell Differentiation process; Cell Maturation; Cells; Chronic; Cicatrix; Colitis; Cues; Data; Dendritic Cells; Environment; Event; FOXP3 gene; Fiber; Funding; Gatekeeping; Generations; Goals; Graft Enhancements; Graft Survival; Heart Transplantation; High Endothelial Venule; Immune; Immune response; Immunity; Immunologics; Immunology; Immunosuppression; Infection; Inflammation; Inflammatory; Inflammatory Response; Integrin alpha6; Intervention; Investigation; Knock-out; Knockout Mice; Laminin; Ligands; Modeling; Mus; Natural Immunity; Outcome; Pathologic; Pathway interactions; Pharmacology; Regulatory T-Lymphocyte; Reticular Cell; Role; Spleen; Stromal Cells; Structure; T cell differentiation; T-Cell Proliferation; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Transcriptional Regulation; Transgenic Organisms; Transplantation; Transplantation Tolerance; Tumor Immunity; Vaccination; adaptive immunity; alpha Dystroglycan; cell motility; chemokine; cohort; effector T cell; insight; interstitial; laminin alpha5; lymph nodes; macrophage; migration; prevent; receptor; response; trafficking

Project Summary/Abstract Foxp3+ regulatory T cells (Treg) are required for transplant tolerance, however, where and when they are induced and activated remains uncertain. During costimulatory blockade induced tolerization, naïve T cells migrate to the lymph node (LN), but not the spleen, where they are stimulated by alloantigen presenting plasmacytoid dendritic cells (pDC), and differentiate into induced Treg (iTreg). We have identified the adhesion and chemokine molecules which orchestrate tolerance by directing the localized accumulation of Treg in the cortical ridge (CR) of the LN where the high endothelial venules (HEV) are present. HEV are the main gatekeeper of T cell trafficking. Overall, naive T cells migrate to the CR and become iTreg, while T cells that become anergic or apoptotic migrate to other regions of the LN. Thus, a unique LN domain is required for the generation and activity of tolerogenic iTreg. The overall hypothesis is that this domain is required for tolerance, and the goal is to define the key events that regulate this structure and can be leveraged for tolerization. In this specialized LN domain the stromal fiber laminin α4:α5 ratios determine the response to alloantigen. Laminins surrounding the HEV and CR act as gatekeepers for T cell fate by directly instructing T cell entry, conversion to iTreg, and the fate of later T cell cohorts, with a high laminin α4:α5 ratio favoring tolerance. Laminin α4 (termed 411 for αβγ chains) promotes CD4 and CD8 T cell motility and transendothelial and interstitial migration into the HEV and CR, promotes Foxp3 expression and iTreg maturation, and inhibits effector T cell differentiation. In contrast, laminin α5 (or 511) inhibits migration into HEV, yet costimulates T cell proliferation and inflammatory Th17. T cells recognize laminin α5 using both integrin α6 and α-dystroglycan (αDG) receptors, and αDG-laminin α5 specifically induces Th17. Antibodies to these receptors prolong graft survival and enhance iTreg migration to the CR. We generalized these concepts in other models (colitis, tumor immunity, chronic rejection, vaccination), and in each case immunity correlated with decreased laminin α4:α5 ratios, while tolerance required an increased ratio. Altogether, our new data indicate that stromal cells regulate the LN laminin α4:α5 ratio and control the fate of the immune response to inflammation and immunity (low ratio) or to suppression and tolerance (high ratio). Our specific hypothesis is that LN stromal cells integrate immune cues and thus regulate laminin structures, and this integration is a final common pathway that channels the immune response and allograft outcomes. Thus, remodeling of laminins is a facet of innate immunity whereby immune cues stimulate stromal cells (FRC, LEC, BEC) to modify LN structure, which subsequently determines adaptive immunity. The corollaries are: 1) laminins regulate the response to inflammation and immunity, which results in pro- inflammatory LN structures or even the pathologic response of immunologic scarring; and 2) laminins regulate the response to suppression and tolerance and result in homeostatic and pro-tolerogenic LN structures.

项目总结/文摘