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).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI132391-02
Application #
9527747
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rothermel, Annette L
Project Start
2017-07-15
Project End
2022-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Florida
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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