TL1A and its receptor DR3 in normal and autoimmune T cell responses

正常和自身免疫 T 细胞反应中的 TL1A 及其受体 DR3

基本信息

批准号：
10023076
负责人：
Richard M Siegel
金额：
$ 50.83万
依托单位：
NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10023076
关键词：
Allergic Allergic Disease Antigens Arthritis Autoimmune Diseases Autoimmune Process Binding Biopsy Bone Diseases Cells Chronic Cleaved cell Colitis Death Domain Dendritic Cells Disease Disease model Extracellular Space FOXP3 gene Family Gene Expression Generations Genotype Goals Haplotypes Homologous Gene Human Immune Immune response Individual Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Innate Immune System Insulin-Dependent Diabetes Mellitus Integral Membrane Protein Interleukin-13 Interleukin-2 Intestines Knockout Mice Lead Ligands Link Mediating Melorheostosis Membrane Metalloproteases Modeling Mus Mutation Necrosis Nematode infections Pathogenesis Pathogenicity Pathologic Pathology Physiological Play Production Psoriasis Publishing RNA Regulatory T-Lymphocyte Research Design Rheumatoid Arthritis Risk Role Signal Pathway Signal Transduction Signaling Protein Site Small Intestines Source Systemic Lupus Erythematosus T cell response T-Lymphocyte T-Lymphocyte Subsets T-cell receptor repertoire TNF gene TNFRSF1A gene TNFSF15 gene TRAMP protein Tissues Toxoplasma gondii Transducers Transgenic Mice Tumor Necrosis Factor Receptor Tumor-infiltrating immune cells Work autoimmune thyroid disease cohort cytokine effector T cell gut microbiota immunopathology immunoregulation member novel polarized cell receptor response risk variant therapeutic target tumor

项目摘要

DR3, also known as TRAMP, LARD, WSL-1, or TNFRSF25, is a death-domain containing tumor necrosis receptor that is the closest homolog to TNF-receptor 1, which is a key transducer of inflammatory responses in the innate immune system. DR3, however, is primarily expressed in T cells. TL1A, the TNF-family ligand for DR3, can costimulate T cells, but the physiological function of TL1A-DR3 interactions in immune responses is not known. In studies published this year, we have shown that DR3 is the critical receptor responsible for TL1A-induced T cell costimulation and that dendritic cells are the likely source for TL1A during T cell priming. Despite its role in costimulation, DR3 is not required for T cell polarization into Th1, Th2 or Th17 effector subtypes or after priming with model antigens or Toxoplasma gondii. However, DR3 is required on T cells for immunopathology, local T cell accumulation and cytokine production in autoimmune and allergic disease models that depend on diverse effector T cell subsets. DR3 is required for efficient T-cell infiltration and immunopathology in inflamed tissues and may be a promising therapeutic target for autoimmune diseases in which T-cells play a pathogenic role, such as Rheumatoid Arthritis, Systemic Lupus Erythematosus, Type-1 diabetes, autoimmune thyroid disease, and others. To better study the type of immune responses stimulated by TL1A, we generated transgenic mice that constitutively express TL1A in T cells or dendritic cells. These mice spontaneously develop IL-13-dependent inflammatory small bowel pathology that strikingly resembles the intestinal response to nematode infections. These changes were dependent on the presence of a polyclonal TCR repertoire, suggesting that they are driven by components in the intestinal flora. FoxP3+ Treg were present in increased numbers despite the fact that TL1A suppresses the generation of inducible Treg. Finally, blocking TL1A-DR3 interactions abrogates TNBS-colitis, indicating that these interactions influence other causes of intestinal inflammation as well. These results establish a novel link between TL1A and IL-13 responses resulting in small intestinal inflammation, and establish that TL1A-DR3 interactions are necessary and sufficient for T cell-dependent inflammatory bowel disease. All TNF-family cytokines are synthesized as type II transmembrane proteins, and most are cleaved by metalloproteinases, releasing soluble cytokine trimers into the extracellular space. We generated TL1A transgenic mice expressing an uncleavable form of TL1A lacking the metalloproteinase cleavage site in T cells (mTL1A transgenic mice). We found that both membrane restricted and soluble TL1A promoted ILC2-mediated allergic intestinal inflammation TL1A. We identified the TNSF15 IBD risk locus as a cis-eQTL, controlling TL1A gene expression. Given the role of TL1A as a T cell costimulator, and the elevation of TL1A expression in IBD intestinal biopsy tissue, one might assume that the risk allele would increase TL1A expression. Surprisingly, using two independent genotyped cohorts of individuals with andwithout IBD, we found that the TNFSF15 risk haplotype decreased, rather than increased, TL1A expression at the RNA level. We have also generated DR3 knockout mice and studies are underway to define the role DR3 in models of arthritis. In related collaborative work, we also investigated a bone disease, melorheostosis and identified mutations MAPK2K1.

DR3，也称为流浪汉，猪油，WSL-1或TNFRSF25，是一种含有肿瘤坏死受体的死亡域，它是最接近TNF-受体1的同源物，它是先天免疫系统中炎症反应的关键传感器。但是，DR3主要在T细胞中表达。 TL1A是DR3的TNF家族配体，可以构成T细胞，但是免疫反应中TL1A-DR3相互作用的生理功能尚不清楚。在今年发表的研究中，我们表明DR3是负责TL1A诱导的T细胞共刺激的关键受体，并且树突细胞可能是T细胞启动过程中TL1A的可能来源。尽管它在共刺激中作用，但T细胞极化不需要Th1，Th2或Th17效应子类型或用模型抗原或弓形虫弓形虫引发。但是，在自身免疫病理学，局部T细胞积累和细胞因子产生的自身免疫性和过敏性疾病模型中，T细胞需要DR3，这些模型依赖于不同的效应T细胞亚群。 DR3是在发炎的组织中有效的T细胞浸润和免疫病理学的有效T细胞所必需的，并且可能是自身免疫性疾病的有前途的治疗靶点，在该疾病中T细胞发挥了致病性作用，例如类风湿性关节炎，全身性狼疮，Erythematosus，e type-1 diabetes，type-1 diabetes，type-1 diabetes，type-1 diabetes，type-type type typerimmmmune throimmune throi dyroids和其他疾病。为了更好地研究TL1A刺激的免疫反应的类型，我们产生了在T细胞或树突状细胞中组成型表达TL1A的转基因小鼠。这些小鼠自发发展IL-13依赖性的炎症小肠病理学，这与对线虫感染的肠反应非常相似。这些变化取决于多克隆TCR库的存在，这表明它们是由肠道菌群中的成分驱动的。尽管TL1A抑制了诱导型Treg的产生，但数量增加了Foxp3+ Treg。最后，阻止TL1A-DR3相互作用消除了TNBS-验证炎，表明这些相互作用也会影响其他肠道炎症的原因。这些结果在TL1A和IL-13反应之间建立了新的联系，导致小肠炎症，并确定TL1A-DR3相互作用是必需的，足以足以用于T细胞依赖性炎症性肠病。所有TNF家庭细胞因子均合成为II型跨膜蛋白，大多数被金属蛋白酶裂解，将可溶性细胞因子夹带释放到细胞外空间中。我们产生了表达TL1A不可泄漏形式的TL1A转基因小鼠，该TL1A缺乏金属蛋白酶裂解位点（MTL1A转基因小鼠）。我们发现膜受限制和可溶性TL1A促进了ILC2介导的过敏性肠炎 TL1A。我们将TNSF15 IBD风险基因座确定为CIS-EQTL，控制TL1A基因表达。鉴于TL1A作为T细胞共临时剂的作用，并且TL1A表达在IBD肠道活检组织中的升高，人们可能会认为风险等位基因会增加TL1A的表达。出乎意料的是，使用和WithIth IBD的两个独立的基因分型人群，我们发现TNFSF15风险单倍型减少而不是增加，而不是增加 RNA水平。我们还产生了DR3敲除小鼠，并正在进行研究以定义关节炎模型中的作用DR3。在相关的协作工作中，我们还研究了骨骼疾病，多鼠菌病并确定了MAPK2K1的突变。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Comparison of gene expression microarray data with count-based RNA measurements informs microarray interpretation.

DOI：
10.1186/1471-2164-15-649
发表时间：
2014-08-04
期刊：
BMC genomics
影响因子：
4.4
作者：
Richard AC;Lyons PA;Peters JE;Biasci D;Flint SM;Lee JC;McKinney EF;Siegel RM;Smith KG
通讯作者：
Smith KG

TL1A and DR3, a TNF family ligand-receptor pair that promotes lymphocyte costimulation, mucosal hyperplasia, and autoimmune inflammation.