Innate Lymphoid Cells in Campylobacter-induced Colitis

Campylobacter is a major human pathogen that infects an estimated 2.5 million people each year resulting in anestimated $1.9 billion economic loss in the U.S. Campylobacter jejuni is a common human enteric pathogen thatcauses acute enterocolitis and increases the risk of developing long-term intestinal dysfunction such as post-infectious irritable bowel syndrome. The innate immune mechanisms responsible for intestinal pathology in C.jejuni-induced colitis are still poorly understood. Innate lymphoid cells (ILCs) are a heterogeneous family of novelregulators of both protective and pathogenic responses in the gut. However, the cellular and molecularmechanisms of protective versus pathogenic responses mediated by distinct populations of ILCs are scantilyunderstood. This gap of knowledge severely limits the development of novel therapies to treat the disease.Therefore, a deeper understanding of the role of ILCs in the pathogenesis of infectious colitis and associatedsequelae is needed to develop better therapeutic approaches that control intestinal inflammation and protectionagainst mucosal pathogens. Our exciting preliminary data strongly suggest that a unique population of IFNγ-producing ILCs that lack natural cytotoxicity receptors (NCR) promotes colitis in a mouse model of C. jejuniinfection. Intriguingly, we revealed that the transcription factor RORγt plays a critical role in the developmentand/or maintenance of these NCR-ILC1s. The overall objective of this proposal is to understand the role of theseILCs in promoting infectious colitis. Our working model is that during the course of C. jejuni infection, ILC3sundergo conversion to a unique population of IFNγ-producing NCR-ILC1s, which promotes intestinal pathology.To test this hypothesis, we propose three specific aims. In Aim 1, we will determine the developmental origin ofpathogenic IFNγ-producing NCR-ILC1s using a genetic cell fate-mapping approach. In Aim 2, we will determinethe colitogenic potential of NCR-ILC1s using an adoptive cell transfer approach. In Aim 3, we will determine therelevance of these NCR-ILC1s to human disease in mice with a reconstituted human immune system. Completionof these aims will lead to a better understanding of the ILC-dependent mechanisms that control intestinalinflammation. The research proposed is significant because it will address a critical gap in our understanding ofthe role of ILCs in promoting intestinal inflammation. Together, this knowledge will guide future efforts to identifytargets to rationally design therapeutic strategies that limit intestinal inflammation. These studies will alsogenerate new knowledge in basic ILC biology in a tractable murine model of a major bacterial pathogen.