Innate lymphoid cells (ILCs) represent an emerging family of cell types that express signature transcription factors, including T-bet+ Eomes+ natural killer (NK) cells, T-bet+ Eomes? type 1 ILCs (ILC1), Gata3+ type 2 ILCs (ILC2), and RORgt+ type 3 ILCs (ILC3). ILCs are abundantly present in mucosal tissues (e.g., lung and gut) at the interface of host-environment interactions. ILC1, ILC2, and ILC3 can readily respond to external stimuli (microbes or dietary components) and produce effector cytokines that mirror their adaptive immune counterparts, Th1, Th2, and Th17/22 cells, respectively. Molecular mechanisms underlying the development and function of ILCs are poorly understood. The aryl hydrocarbon receptor (Ahr) is a ligand-dependent transcription factor, best known to mediate the effects of xenobiotic environmental toxins and endogenous microbial and dietary metabolites. We and others have shown that Ahr is required for ILC3 maintenance and function. Our preliminary data revealed tissue-specific expression of Ahr in ILCs and differential regulation of ILC differentiation and function by Ahr in the gut. We hypothesize that Ahr regulates the ILC2-ILC3 balance in the gut, thus impacting intestinal inflammation and immunity. Specifically, we will investigate 1) the regulation of Ahr expression in ILCs, 2) the molecular mechanism(s) by which Ahr regulates the ILC2-ILC3 balance in the gut, and 3) the functional role of Ahr in regulation of ILCs in DSS-induced gut injury. These experiments will offer an opportunity to elucidate environmental impacts on gut inflammation and immunity via the Ahr-mediated pathway. Our study will provide novel cellular and molecular insights into the development and function of ILCs regulated by Ahr in a tissue- and cell-specific manner. Since Ahr is a ligand-dependent transcription factor and its activity can be regulated by small molecules, modulating Ahr expression and/or function in ILCs may represent a new paradigm for human disease treatment or prevention (e.g., inflammatory bowel disease, enteric infections, and allergic diseases).

Public Health Relevance

Innate lymphoid cells (ILCs) play an important role in inflammation and autoimmunity. The proposed experiments will provide novel insights into the molecular mechanisms of action of the aryl hydrocarbon receptor (Ahr), an environmental sensor, in the regulation of ILC differentiation and function, and into the role of Ahr in gut inflammation and immunity. Better understanding of ILC biology regulated by Ahr may eventually provide novel means to treat human disease (e.g., inflammatory bowel disease, pathogen infections and allergic diseases).

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Rothermel, Annette L
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University of Florida
Schools of Veterinary Medicine
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Li, Shiyang; Bostick, John W; Ye, Jian et al. (2018) Aryl Hydrocarbon Receptor Signaling Cell Intrinsically Inhibits Intestinal Group 2 Innate Lymphoid Cell Function. Immunity 49:915-928.e5
Zhou, Sha; Qi, Qianqian; Wang, Xiaofan et al. (2018) SjHSP60 induces CD4+ CD25+ Foxp3+ Tregs via TLR4-Mal-drived production of TGF-? in macrophages. Immunol Cell Biol 96:958-968
Ye, Jian; Qiu, Ju; Bostick, John W et al. (2017) The Aryl Hydrocarbon Receptor Preferentially Marks and Promotes Gut Regulatory T Cells. Cell Rep 21:2277-2290
Li, Shiyang; Bostick, John W; Zhou, Liang (2017) Regulation of Innate Lymphoid Cells by Aryl Hydrocarbon Receptor. Front Immunol 8:1909