Regulatory T Cells and Lymphatic Endothelial Cells: Regulatory Interactions for Migration and Suppression

调节性 T 细胞和淋巴内皮细胞：迁移和抑制的调节相互作用

• 批准号: 10595634
• 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: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595634
• 关键词: Adenosine; Adoptive Transfer; Antigen Receptors; Antigens; Area; Autoimmunity; Binding; Blood; Blood Vessels; CCL21 gene; CD4 Positive T Lymphocytes; Cell Communication; Cell surface; Data; Dendritic Cells; Development; Endothelial Cells; Endothelium; Event; FOXP3 gene; Funding; Gatekeeping; Geography; Goals; Helper-Inducer T-Lymphocyte; Homeostasis; IL2RA gene; Immune response; Immunity; Immunology; Infection; Inflammation; Interleukin-6; Interruption; Investigation; Islets of Langerhans Transplantation; Kinetics; Leukocytes; Ligands; Lymphatic; Lymphatic Endothelial Cells; Lymphatic Endothelium; Lymphocyte; Lymphoid Tissue; Malignant Neoplasms; PD-1/PD-L1; Peripheral; Phenotype; Phosphotransferases; Production; Publications; Receptor Cell; Receptor Signaling; Regulatory T-Lymphocyte; Resolution; Role; Signal Pathway; Signal Transduction; Site; Stimulus; Structure; System; Therapeutic; Thymus Gland; Time; Tissues; Transplantation; Transplantation Tolerance; Tumor Necrosis Factor-Beta; Vaccination; Vascular Cell Adhesion Molecule-1; Vascular Endothelium; allograft rejection; conditioning; draining lymph node; isoimmunity; migration; novel; pathogen; permissiveness; polarized cell; programmed cell death ligand 1; programmed cell death protein 1; receptor; response; trafficking; transcription factor

Project Summary/Abstract Foxp3+ regulatory CD4+ T cells (Treg) induce and maintain tolerance. Treg also limit the tempo and strength of normal immune responses to environmental antigens and pathogens. How Treg are regulated to manifest these functions is incompletely understood. Treg co-opt helper T cell (Th) transcription factors to express similar selected receptors and migrate to Th resident sites to suppress immunity. Since Treg and Th responses are not precisely aligned, these observations do not fully define mechanisms of how Treg are regulated, nor identify how their function is channeled to be in the “right place at the right time”. The mechanisms of how Treg functions are geographically and kinetically distinct from conventional CD4+ T cells (Tconv) remain elusive. We demonstrated that specific trafficking is required for Treg to suppress allograft rejection: Treg sequentially migrate from blood through microvascular endothelium into tissue, and then from tissue through afferent lymphatics to the draining lymph nodes (dLN). If this sequence is interrupted, particularly lymphatic migration, Treg fail to be activated and suppress Tconv and dendritic cells (DC) in tissue and LN. Indeed, Treg lose CD25 and Foxp3, becoming exTreg. Thus, a major requirement for normal Treg function, and a step not required for Tconv, is afferent lymphatic migration. Our overall hypothesis is that the Treg-lymphatic interaction is an important regulatory nidus for suppression and tolerance, and our goal is to define the key events and structures that regulate this interaction. Our publications demonstrate novel attributes of Treg migration. Thymus derived (nTreg) and peripherally induced Treg (iTreg) express high cell surface lymphotoxin  (LT). Treg use LT to migrate across afferent lymphatic endothelial cells (LEC). Treg LT binds the LEC LT-receptor (LTR) to stimulate non-canonical NFB-inducing kinase (NIK). NIK signaling facilitates Treg transendothelial migration (TEM) by inducing LEC responses, including increased CCL21 expression, VCAM-1 rearrangement, and basal lamellipodia that engage Treg. Our new studies show that the Treg-LEC interaction: 1.) uses LT-LTR to condition LEC for permissiveness for gating the TEM of other leukocytes (i.e. T, B, DC, M); 2.) determines if exTreg are induced; and 3.) relies on PD-1(Treg)/PD-L1(LEC) interactions for Treg TEM. Our data demonstrate novel Treg-LEC interactions that serve essential roles for Treg suppression. Since Treg must migrate through tissues and interact with afferent lymphatics, and since Treg uniquely deploy diverse interactions with LEC that regulate migration and suppression, these observations lead us to the following specific hypotheses: 1.) Treg-LEC LT-LTR interactions regulate the permissiveness of LEC for gating TEM of many other leukocyte subsets and acts as a gatekeeper for immunity, suppression, and resolution of inflammation; 2.) Treg-LEC interactions determine if Treg maintain suppressive functions or become exTreg; and 3.) Treg-LEC TEM relies on a novel role for PD-1/PD-L1.

项目摘要/摘要 FOXP3+调节性CD4+ T细胞（TREG）影响并保持耐受性。 Treg还限制了节奏 正常免疫回应对环境抗原和病原体的强度。如何调节Treg 表现出这些功能是不完全理解的。 Treg Co-Opt辅助T细胞（Th）转录因子 表达相似的选定接收器，并迁移到居民站点以抑制免疫力。自从Treg和Th以来 响应不是精确对齐的，这些观察结果并未完全定义Treg的机制 受监管，也没有确定如何将其功能引导到“正确的时间正确的位置”。 Treg功能的机制在地理和动力学上与传统不同 CD4+ T细胞（TCONV）仍然难以捉摸。我们证明了Treg抑制需要特定的贩运 同种异体移植排斥：Treg顺序从血液通过微血管森植物迁移到组织，然后 然后从组织到传入淋巴细胞癌到排水淋巴结（DLN）。如果此序列被中断， 特别是淋巴迁移，未能激活Treg并抑制组织中的TCONV和树突状细胞（DC） 和ln。的确，Treg失去了CD25和Foxp3，变得超越。那是正常treg的主要要求 功能，TCONV不需要的步骤是传入的淋巴迁移。我们的总体假设是 Treg淋巴相互作用是抑制和耐受性的重要调节性nidus，我们的目标是 定义调节这种相互作用的关键事件和结构。 我们的出版物展示了Treg迁移的新属性。胸腺衍生（Ntreg）和 外周诱导的Treg（ITREG）表达高细胞表面淋巴毒素（LT）。 treg使用lt迁移 跨传入淋巴内皮细胞（LEC）。 treglt结合LECLT受体（LTR）刺激 非典型的NFB诱导激酶（NIK）。 NIK信号传导通过 诱导的LEC反应，包括增加CCL21表达，VCAM-1重排和基本 吸引treg的薄片。我们的新研究表明，Treg-Lec相互作用：1。）使用lt-ltr 条件LEC，可允许门控其他白细胞的TEM（即t，b，dc，m）； 2.）确定是否 诱发了外来；和3.）依赖于Treg TEM的PD-1（Treg）/PD-L1（LEC）相互作用。我们的数据 演示新型的Treg-Lec相互作用，这些相互作用起着Treg抑制的重要作用。 由于Treg必须通过组织迁移并与传入淋巴细胞相互作用，并且Treg唯一 与调节迁移和抑制的LEC部署各种互动，这些观察结果使我们成为 以下特定假设：1。）treg-leclt-ltr相互作用调节LEC的允许性 对于许多其他白细胞子集的门控tem，并充当免疫，抑制和 炎症的解决； 2.）Treg-Lec相互作用确定Treg是否保持抑制功能或 脱颖而出； 3.）Treg-Lec tem依赖于PD-1/PD-L1的新作用。