A Role for the Aryl Hydrocarbon Receptor in the Development of IL-22 Producing Innate Lymphoid Cells

A Role for the Aryl Hydrocarbon Receptor in the Development of IL-22 Producing Innate Lymphoid Cells by Jacob S. Lee Doctor of Philosophy in Immunology Washington University in St. Louis, 2013 Professor Marco Colonna, Chairperson The intestinal mucosal immune system comprises a well organized and intricate network of intestinal epithelium, innate and adaptive immune cells. The coordinated actions of the intestinal immune system is absolutely critical for maintaining a fine balance between the trillions of endogenous commensal microorganisms and the host, while also contributing to protection against invading and harmful pathogens. A properly functioning host-commensal bacteria relationship ensures the proper extraction of nutrients from food, fortification against invading pathogens, and protection from inflammatory and metabolic diseases. Among the various immune cells vital to this task, innate lymphoid cells (ILCs) contribute an essential role in maintaining this homeostatic balance. This dissertation investigates the function of these recently identified population of ILCs termed group 3 ILCs, which include NKp46+ and lymphoid tissue inducer (LTi)-like subsets, as well as describing and characterizing the aryl hydrocarbon receptor (AHR) as a key transcription factor necessary for their development. Mice with a specific deletion of AHR in ILCs had greatly reduced numbers of mucosal group 3 ILCs, and increased susceptibility to bacterial infections. The specific loss of the NKp46+ILC subset did not result in any increase in susceptibility to bacterial infection, suggesting overlapping or redundant functions within the group 3 ILCs. However, depletion of the NKp46+ILC subset may offer protection from CD40 and dextran sodium sulfate (DSS) mediated models of colitis demonstrating a pathogenic potential of these ILCs in certain contexts. Ahr-/- mice also lacked post-natally imprinted cryptopatches (CPs) and isolated lymphoid follicles (ILFs), but embryonically imprinted Peyer\u27s Patches (PP) was intact. Notch was a key transcription factor downstream of AHR, and the specific ablation of Notch signaling in ILCs resulted in a block in their development. The search for potential AHR agonists is also described in this dissertation. Treatment with antibiotics or germ-free animals did not alter the group 3 ILC populations nor did it impact their function, thus excluding the role of the microbiota as a potential source of AHR ligands. While treatment with many different AHR agonists were experimentally investigated both in vitro and in vivo, none of the ligands tested thus far had a significant impact on the group 3 ILC subsets in terms of their frequency or function, suggesting a much more complicated task of understanding the AHR signaling pathway in the development of group 3 ILCs. Taken together, this dissertation describes the specific function of group 3 ILCs during host defense to bacterial pathogens, exploring the pathogenic potential of group 3 ILCs during inflammatory conditions as well as the novel finding of AHR as a key transcription factor in the development of group 3 ILCs