TL1A Regulation of Group 3 Innate Lymphoid Cells in Colitis

炎症性肠病（IBD）影响全世界超过400万人，导致显著的发病率。一 需要对疾病的细胞和遗传机制有更深入的了解， 更安全、更有效的治疗方法。第3组先天性淋巴样细胞（ILC 3）在免疫系统中起核心作用。 IBD的病理生理学作为IL-22的主要生产者，我们和其他人已经显示了ILC 3在以下方面的关键作用： 促进IBD的粘膜愈合;然而，除了它们的保护作用外，炎性ILC 3的一个子集 也会导致肠道炎症。增加了这种复杂性，MHCII+ ILC 3可以作为抗原呈递 组织中的T细胞限制了对唾液的T细胞免疫。关键的知识差距存在于理解 在IBD中调节ILC 3的异质性功能的组织衍生因子。我们之前已经展示了 肠CX 3CR 1+单核吞噬细胞（MNP）作为粘膜的哨兵，产生IL-23， 在体内调节组织保护性ILC 3应答。定义可能调节ILC 3的关键MNP衍生因子 在免疫方面，我们先前发表的工作鉴定了人肠MNP的TNFSF 15的高表达。在 患有IBD的患者，TNFSF 15基因变异赋予更高的侵袭性疾病并发症的风险。 TNFSF 15蛋白，称为TNF样细胞因子1A（TL 1A），在活动期的人结肠组织中高度表达。 结肠炎和我们发表的数据表明TL 1A调节ILC 3效应细胞因子的产生。因此 本提案的目的是评估TL 1A在规范国际法委员会基本方面的核心作用3 生物学初步数据表明，MNP是TL 1A的主要生产者， TL 1A与IL-23协同作用以促进IL-22的保护性ILC 3产生。另外，我们发现， TL 1A诱导的共刺激分子OX 40 L使MHCII+ ILC 3能够激活肠道T细胞- 扩展了ILC 3调节粘膜免疫的模型。我们的中心假设是TL 1A是一种 IBD中的中枢调节粘膜ILC 3免疫，通过促进先天ILC 3效应子功能， MNP-ILC 3在组织中相互作用，并刺激ILC 3控制粘膜T细胞免疫。我们将 本研究的主要目的是：（1）探讨TL 1A对ILC 3基因表达的调控作用 结肠炎的功能。(2)确定MNP衍生的TL 1A在协调粘膜ILC 3功能中的作用。(3)到 确定TL 1A诱导的OX 40 L在调节适应性T细胞免疫的ILC 3控制中的作用。拟议 研究将使用新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ILC 3免疫。这些目标的预期成果将确定TL 1A和MNP- 衍生的TL 1A作为先天ILC 3效应子功能、MNP-ILC 3相互作用和ILC 3控制的中心调节物， 粘膜T细胞免疫如果成功，这项工作将确立IBD相关TL 1A在以下方面的核心作用： 调节ILC 3免疫的基本特征，这将有助于指导IBD的治疗策略。

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.