Endogenous TLR1 signals prevent uncontrolled innate immunity in the colon

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 DESCRIPTION (provided by applicant): The intestine is a complex organ home to one of our body's largest immune system networks, 100 trillion commensal bacteria, and a variety of specialized eukaryotic cells, such as epithelium, Paneth cells and mucus- producing goblet cells. A high antigenic burden in the intestine exists because it is a common entry site for pathogens, the site for absorption of food proteins and the high number of commensal bacteria. Dysregulation of the immune responses can lead to disease such as inflammatory bowel disease (IBD) or colitis-associated cancers. In order to prevent aberrant immune responses communication and regulation between these compartments is essential. The close proximity of the microbial world to the human cells of our intestine suggest that innate receptors, such as Toll-like Receptors (TLR), which recognize conserved microbial motifs, may play an essential role in regulating homeostasis and inflammation. Our previous work has identified TLR1 as a critical mediator of intestinal immunity during pathogenic infection. Further, we have found that a single nucleotide polymorphism in TLR1, which abrogates surface expression and signaling, is associated with pediatric IBD. Further this mutation impacts disease severity and response to immune-therapies. Intriguingly, we have found that naïve mice deficient for TLR1 signaling produce elevated levels of the pro-inflammatory innate cytokines IL-23 and IL-1ß in the colonic lamina propria. IL-23 and IL-1ß are important for the expansion and maintenance of TH17 cells and group 3 innate lymphoid cells (ILC3). We have found that homeostatic levels of TH17 cells are normal, however ILC3 are significantly increased in the colons of TLR1-deficient mice. Importantly ILC have been identified in patients with IBD, though their induction, regulation and role are still unknown. The proposed research will examine the regulation of IL-23 and IL-1ß in the absence of endogenous TLR1 signaling in the colon and how this impacts the development of ILC3. Specifically, we will determine whether IL-1ß and IL-23 are necessary and sufficient for the homeostatic increase in ILC3 and determine the cell types necessary for this increase. We will also determine how the absence of TLR1 signaling in the colon leads to up-regulated IL-23 and IL-1ß. Lastly, as ILC can have both protective and pathogenic roles in the colon, we will examine how ILC induced in the absence of TLR1 signaling impacts intestinal inflammatory responses. The results of these studies will contribute to the understanding how specific TLR1 signals regulate of innate immunity in the colon. Further, as we have identified a mutation in TLR1 signaling in pediatric patients with IBD, a greater understanding of the regulation of innate immunity by TLR1 may lead to the development of individualized therapies or treatments to prevent disease or relapses.