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

• 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
• 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

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)影响全球400多万人，导致显著的发病率。一个 需要对疾病背后的细胞和遗传机制有更深的了解，才能设计出有针对性的 更安全、更有效的疗法。第3组先天淋巴样细胞(ILC3)在 IBD的病理生理学。作为IL-22的主要生产者，我们和其他人已经展示了ILC3在 促进IBD的粘膜愈合；然而，除了它们的保护作用外，炎症性ILC3的亚群 也会导致肠道发炎。增加这种复杂性的是，MHCII+ILC3可以作为抗原递呈 组织中的细胞将T细胞免疫限制为共生体。在理解上存在一个关键的知识鸿沟 调节IBD中ILC3异源功能的组织衍生因子。我们之前已经展示了 肠道CX3CR1+单核巨噬细胞(MNPs)作为粘膜的哨兵，产生IL-23，并 在体内调节组织保护性ILC3反应。确定可能调节ILC3的MNP衍生关键因子 免疫，我们先前发表的工作发现人肠道MNPs高表达TNFSF15。在……里面 患有IBD、TNFSF15基因变异的患者发生更具侵袭性的疾病并发症的风险更高。 TNFSF15蛋白被称为肿瘤坏死因子样细胞因子1A(TL1A)，在活动性结肠组织中高表达 结肠炎和我们发表的数据表明，TL1A调节ILC3效应器细胞因子的产生。因此， 本提案的目的是评估TL1A在调节ILC3基本方面的核心作用 生物学。初步数据显示，MNPs是TL1a和TL1a的主要生产者，这一提议得到了支持 TL1a与IL-23协同促进IL-22产生保护性ILC3。另外，我们发现， TL1a-共刺激分子OX40L的诱导使MHCII+ILC3s能够激活肠道T细胞- 拓展ILC3s调节黏膜免疫的模型。我们的中心假设是TL1a是一个 中枢调节因子ILC3在IBD黏膜免疫中促进先天ILC3效应功能 MNP-ILC3在组织内相互作用，并刺激ILC3控制粘膜T细胞免疫。我们会 评估这一假说的目的如下：(1)评估TL1A在调节先天ILC3中的作用 在结肠炎中的作用。(2)确定MNP来源的TL1a在协调黏膜ILC3功能中的作用。(3)至 确定TL1A诱导的OX40L在调节ILC3调控适应性T细胞免疫中的作用。建议数 研究将使用新的老鼠模型和独特的人类样本来从根本上推进我们的基本 对IBD患者ILC3免疫功能的认识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控制的中央调节因子 粘膜T细胞免疫。如果成功，这项工作将建立与IBD相关的TL1a在 调节ILC3免疫的基本特征，将有助于指导IBD的治疗策略。