TL1A Regulation of Group 3 Innate Lymphoid Cells in Colitis

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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.