TL1A Regulation of Group 3 Innate Lymphoid Cells in Colitis

Weill Medical Coll Of Cornell Univ, New York NY

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Abstract

Inflammatory bowel disease (IBD) affects millions of people worldwide, causing significant morbidity. Despite improvements in medical therapy, nearly one-third of IBD patients develop refractory disease requiring hospitalization or surgery. The long-term goal of this proposal is to identify the cellular and molecular mechanisms underlying disease in order 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, ILC3s play a critical role in promoting mucosal healing in IBD2. Emerging data, however, has revealed that ILC3s can function as a double-edged sword, driving tissue inflammation in mouse models of colitis and IBD. In addition to these innate effector functions, recent studies have revealed that MHCII+ RORt+ ILCs can act as antigen presenting cells (APCs) which limit T cell responses against commensal bacteria and promote regulatory T cells. The objective of this proposal is to define the molecular and cellular mechanisms that regulate these heterogenous functions of ILCs in IBD. Our published and preliminary data identify TNF-like cytokine 1A (TL1A) as central regulator of these heterogenous function of ILC3s. TL1A is highly expressed in human colonic tissue during IBD and variants in TNFSF15, the genetic locus that encodes TL1A, confer higher risk for more aggressive disease complications. While early studies showed a pathogenic role for TL1A in driving inflammatory T cell responses, subsequent work from our own group and others have revealed a direct role for TL1A in regulating ILCs. Using RNA-seq of TL1A-stimulated intestinal ILC3, our preliminary data reveal that TL1A signaling robustly and specifically induce expression of the transcription factor Bhlhe40. Bhlhe40 is a member of the basic helix- loop-helix TF family, which is a key regulator of cytokine production by macrophages and T cells. Bhlhe40 is required for inflammation and promotes immune responses in autoimmunity, transplantation, and cancer. Single cell data identified Bhlhe40 in intestinal ILCs, but the potential role of Bhlhe40 in ILC3 is unknown. Using new genetic mouse models and human biopsy samples, this proposal will test the hypothesis that Bhlhe40 in ILC3s is critical in shaping innate immunity to in inflammatory colitis as well as coordinating mucosal cellular responses to maintain antigen specific tolerance in the intestine. The expected outcomes of these aims are to identify a new role for Bhlhe40 in shaping innate effector functions of ILC3s and revealing a central role for intestinal ILC3s in coordinating cellular immunity to enforce intestinal tolerance. If successful, these findings will uncover new mechanistic targets for regulating ILC3s in IBD.