The human immune system must remain in constant balance to be healthy. Elevated immune responses are needed to fight harmful microorganisms, yet those same responses have to be kept from overreacting and attacking the body's normal tissues. A complex mix of immune cells is known to influence this balance. Among them, Th17 cells, a newly defined T cell subset (a group of white blood cells), are important to clear certain bacterial or fungal infections, whereas dysregulated Th17 responses can cause many human autoimmune diseases, such as inflammatory bowel disease (IBD). Regulatory T cells (Treg) have been discovered to control the detrimental effects of effector T cells including Th17 cells. The balance between Th17 and Treg cells influenced by interplay among transcription factors is most readily visible in the intestinal environment and is crucial for maintenance of gut immune stability. The aryl hydrocarbon receptor (AhR), best known for mediating the effects of environmental toxins, is one of the most upregulated transcription factors in Th17 cells. AhR promotes Th17 cell differentiation, and is also likely involved in Treg differentiation, thus modulating the Th17-Treg balance. AhR can be activated by environmental toxins and by natural compounds generated by bacteria normally living in the intestines. Therefore, identification of a role for AhR in Th17 biology would provide a fascinating link among environmental factors, gut microbiota, and human immunological diseases, but the precise role of AhR in infection and inflammation remains to be determined. My long-term research goal is dedicated to identifying the molecular means to modulate the balance of inflammatory and anti-inflammatory cells, thereby combating infection and preventing autoimmunity. In this proposal, we will test a new hypothesis that AhR plays a crucial role in gut immunity by influencing Th17 and Treg cell differentiation, and the differential impact on individual Th17 cytokine expression by AhR may influence IBD pathogenesis. T cell transfer model of chronic colitis, a mouse model that mimics human IBD, will be used. We will utilize loss-of-function and gain-of-function approaches to test the hypothesis by pursuing the following three specific aims: 1) Characterize AhR-deficient T cell induced colitis. 2) Determine whether attenuating Th1 or Th17 responses can ameliorate AhR-deficient T cell transfer-mediated colitis. 3) Determine the role of AhR in Treg differentiation and function in colitis pathogenesis. The knowledge gained from our proposed study will shed light on how to modulate the activity of a transcription factor to maintain the stability of the intestinal immune system and thereby prevent a variety of debilitating diseases. Since activation of AhR requires binding to certain molecules (i.e. ligands), the results of this project may allow us to identify new drug targets and develop small compounds to regulate AhR activity for therapeutic intervention in human immunological diseases.

Public Health Relevance

The study proposed here will take the first steps toward novel insights into the action of a transcription factor, AhR, in intestinal immune equilibrium, and shed light on the role of AhR in the pathogenesis of inflammatory bowel disease. A better understanding of the role of AhR in the immune system may eventually provide novel means for treating human infectious and autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI091962-02
Application #
8217073
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Esch, Thomas R
Project Start
2011-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$190,625
Indirect Cost
$65,625
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Zhou, Liang (2016) AHR Function in Lymphocytes: Emerging Concepts. Trends Immunol 37:17-31
Stefka, Andrew T; Feehley, Taylor; Tripathi, Prabhanshu et al. (2014) Commensal bacteria protect against food allergen sensitization. Proc Natl Acad Sci U S A 111:13145-50
Guo, Xiaohuan; Qiu, Ju; Tu, Tony et al. (2014) Induction of innate lymphoid cell-derived interleukin-22 by the transcription factor STAT3 mediates protection against intestinal infection. Immunity 40:25-39
Heller, Jennifer J; Schjerven, Hilde; Li, Shiyang et al. (2014) Restriction of IL-22-producing T cell responses and differential regulation of regulatory T cell compartments by zinc finger transcription factor Ikaros. J Immunol 193:3934-46
Qiu, Ju; Zhou, Liang (2013) Aryl hydrocarbon receptor promotes ROR?t? group 3 ILCs and controls intestinal immunity and inflammation. Semin Immunopathol 35:657-70
Do-Umehara, Hanh Chi; Chen, Cong; Urich, Daniela et al. (2013) Suppression of inflammation and acute lung injury by Miz1 via repression of C/EBP-?. Nat Immunol 14:461-9
Qiu, Ju; Guo, Xiaohuan; Chen, Zong-Ming E et al. (2013) Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity 39:386-99
Ueda, Aki; Zhou, Liang; Stein, Paul L (2012) Fyn promotes Th17 differentiation by regulating the kinetics of ROR?t and Foxp3 expression. J Immunol 188:5247-56
Qiu, Ju; Heller, Jennifer J; Guo, Xiaohuan et al. (2012) The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36:92-104
Zhou, Liang (2012) Striking similarity: GATA-3 regulates ILC2 and Th2 cells. Immunity 37:589-91

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