TL1A Regulation of Group 3 Innate Lymphoid Cells in Colitis

TL1A 对结肠炎中第 3 组先天淋巴细胞的调节

基本信息

批准号：
10357907
负责人：
randy s longman
金额：
$ 38.14万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-10 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357907
关键词：
Affect Antigen-Presenting Cells Antigens Autoimmune Diseases Biopsy Specimen Cell Communication Cell physiology Cells Cellular biology Chronic Colitis Cues Data Disease Effector Cell Functional disorder Genes Genetic Human Immunity In Vitro Inflammatory Inflammatory Bowel Diseases Intestines Knowledge Link Lymphoid Cell Modeling Mononuclear Morbidity - disease rate Mucosal Immune System Mucosal Immunity Mucositis Mucous Membrane Mus Outcome Pathogenesis Patients Persons Phagocytes Play Production Proteins Publishing Regulation Reporter Role Sampling Sentinel Signal Transduction Supporting Cell System T cell response T-Lymphocyte TNF gene TNFSF15 gene TNFSF4 gene Testing Therapeutic Tissue Sample Tissues Tumor Necrosis Factor Receptor Variant Work antigen-specific T cells biobank cellular targeting cytokine design experimental study genetic variant gut inflammation healing high risk human tissue improved in vivo interleukin-22 interleukin-23 link protein microbial mouse model novel response targeted treatment

项目摘要

Inflammatory bowel disease (IBD) affects over 4 million people worldwide, causing significant morbidity. A deeper understanding of the cellular and genetic mechanisms underlying disease are needed to design targeted therapies that are safer and more effective. Group 3 innate lymphoid cells (ILC3s) play a central role in the pathophysiology of IBD. As the major producers of IL-22, we and others have shown a critical role for ILC3s in promoting mucosal healing in IBD; however, in addition to their protective role, a subset of inflammatory ILC3s can also drive intestinal inflammation. Adding to this complexity, MHCII+ ILC3s can act as antigen presenting cells in the tissue limiting T cell immunity to commensals. A critical knowledge gap exists in understanding tissue-derived factors that regulate the heterogenous functions of ILC3s in IBD. We have previously shown the intestinal CX3CR1+ mononuclear phagocytes (MNPs) acts as sentinels of the mucosa, produce IL-23, and regulate the tissue protective ILC3 response in vivo. To define key MNP-derived factors that may regulate ILC3 immunity, our previously published work identified high expression of TNFSF15 by human intestinal MNPs. In patients with IBD, TNFSF15 gene variants confer higher risk for more aggressive disease complications. TNFSF15 protein, called TNF-like cytokine 1A (TL1A), is highly expressed in human colonic tissue during active colitis and our published data suggests that TL1A regulates ILC3 effector cytokine production. Therefore, the objective of this proposal is to evaluate the central role for TL1A in regulating fundamental aspects of ILC3 biology. This proposal is supported by preliminary data showing that MNPs are the main producers of TL1A and that TL1A synergizes with IL-23 to promote protective ILC3 production of IL-22. In addition, we discovered that TL1A-induction of the co-stimulatory molecule OX40L enables MHCII+ ILC3s to activate intestinal T cells— expanding the model by which ILC3s regulate mucosal immunity. Our central hypothesis is that TL1A is a central regulator mucosal ILC3 immunity in IBD by promoting innate ILC3 effector function, enabling MNP-ILC3 interaction in the tissue, and stimulating ILC3 control of mucosal T cell immunity. We will evaluate this hypothesis with the following aims: (1) To evaluate the role for TL1A in regulating innate ILC3 function in colitis. (2) To determine the role for MNP-derived TL1A in coordinating mucosal ILC3 function. (3) To determine the role for TL1A-induced OX40L in regulating ILC3 control of adaptive T cell immunity. The proposed studies will use novel mouse models and unique human samples to fundamentally advance our basic understanding of ILC3 immunity in IBD. The expected outcomes of these aims will identify TL1A and MNP- derived TL1A as a central regulator of innate ILC3 effector function, MNP-ILC3 interaction, and ILC3 control of mucosal T cell immunity. If successful, this work will establish the central role for the IBD-linked TL1A in regulating fundamental features of ILC3 immunity that will help guide therapeutic strategies for IBD.

炎症性肠病 (IBD) 影响着全球超过 400 万人，导致高发病率。需要更深入地了解疾病背后的细胞和遗传机制来设计靶向药物更安全、更有效的第 3 类先天淋巴细胞 (ILC3) 疗法在治疗中发挥着核心作用。作为 IL-22 的主要生产者，我们和其他人已经证明 ILC3 在 IBD 的病理生理学中发挥着关键作用。然而，除了其保护作用外，炎症性 ILC3 的一个子集还促进 IBD 的粘膜愈合；更复杂的是，MHCII+ ILC3 还可以充当抗原呈递作用。组织中的细胞限制了共生体的 T 细胞免疫，但在理解方面存在着关键的知识差距。调节 IBD 中 ILC3 异质功能的组织源性因子肠道CX3CR1+单核吞噬细胞（MNP）充当粘膜的哨兵，产生IL-23，并调节体内组织保护性 ILC3 反应定义可能调节 ILC3 的关键 MNP 衍生因子。免疫方面，我们之前发表的工作发现人肠道 MNPs 高表达 TNFSF15。对于 IBD 患者，TNFSF15 基因变异会带来更高的侵袭性疾病并发症风险。 TNFSF15蛋白，称为TNF样细胞因子1A（TL1A），在活动期间在人结肠组织中高表达。结肠炎和我们发表的数据表明 TL1A 调节 ILC3 效应细胞因子的产生。该提案的目的是评估 TL1A 在调节 ILC3 基本方面的核心作用该提议得到了初步数据的支持，表明 MNP 是 TL1A 和 TL1A 的主要生产者。 TL1A 与 IL-23 协同作用，促进保护性 ILC3 产生 IL-22。 TL1A 诱导共刺激分子 OX40L 使 MHCII+ ILC3 能够激活肠道 T 细胞 — 扩展 ILC3 调节粘膜免疫的模型我们的中心假设是 TL1A 是一个 IBD 中枢调节器粘膜 ILC3 免疫通过促进先天 ILC3 效应器功能，使 MNP-ILC3 在组织中相互作用，并刺激 ILC3 对粘膜 T 细胞免疫的控制。评估该假设的目的如下： (1) 评估 TL1A 在调节先天 ILC3 中的作用 (2) 确定 MNP 衍生的 TL1A 在协调粘膜 ILC3 功能中的作用。确定 TL1A 诱导的 OX40L 在调节 ILC3 控制适应性 T 细胞免疫中的作用。研究将使用新颖的小鼠模型和独特的人类样本从根本上推进我们的基础研究了解 IBD 中的 ILC3 免疫力，这些目标的预期结果将确定 TL1A 和 MNP-。衍生的 TL1A 作为先天 ILC3 效应器功能、MNP-ILC3 相互作用和 ILC3 控制的中央调节器如果成功，这项工作将确立 IBD 相关 TL1A 在粘膜 T 细胞免疫中的核心作用。调节 ILC3 免疫的基本特征将有助于指导 IBD 的治疗策略。