P075 - MICROBIAL INDUCTION OF TL1A LINKS PROTECTIVE AND PATHOGENIC ROLES FOR GROUP 3 INNATE LYMPHOID CELLS IN COLITIS
(Room Poster Hall)
19 Jan 18
5:30 PM
-
7:00 PM
Tracks:
Clinical and Research Challenges
Background: Inflammatory bowel disease (IBD) results from a dysregulated interaction between the microbiota and a genetically susceptibe host. Polymorphisms in the TNFSF15 locus link TNF-like ligand 1A (TL1A) with IBD, but the functional impact of TL1A in regulating barrier immunity and intestinal inflammation is not clear. Methods: Here, we used cell-specific genetic deletion and gnotobiotic mouse models to evaluate the role for microbial induced TL1A signaling through death receptor 3 (DR3) in group 3 innate lymphoid cell (ILC3) in colitis. Flow cytometry, RNA-seq, and antigen specific proliferation assays are used to examine the mechanistic and functional impact of TL1A signaling in ILC3s. Results: These novel genetic models revealed an essential protective role for TL1A regulation of group 3 innate lymphoid cell (ILC3) production of IL-22 in acute colitis. Intestinal CX3CR1+ macrophage production of TL1A is induced by IBD-associated adherent microbiota and promoted ILC3-dependent mucosal healing in vivo. In addition to regulating IL-22 production, colitis induced DR3-dependent expression of co-stimulatory molecules on MHCII+ ILC3. In contrast to the protective role in acute colitis, TL1A stimulation of ILC3 enabled co-stimulation dependent antigen specific T cell priming and exacerbated chronic T cell-dependent colitis. Conclusions: These dual effects of TL1A in acute and chronic colitis highlight a central role for this pathway in regulating ILC3 contribution to barrier immunity and will help guide TL1A-based diagnostic and therapeutic approaches to IBD.