Possible Role for the Ah Receptor in the Generation of Regulatory T Cells

Nancy I. Kerkvliet, Ph.D. and Castle J. Funatake
Oregon State University
P01ES00040, P30ES00210, and T32ES07060

Background: The aryl hydrocarbon (Ah) receptor is a remarkable member of the PAS family of transcription factors that are involved in responding to a wide variety of environmental stimuli such as oxygen partial pressure, light intensity, and xenobiotic compounds. Adding to the complex nature of the receptor, it was recently shown to be involved in the closure of a fetal vascular shunt known as the ductus venosus. The environmental contaminant, tetrachlorodibenzodioxin (TCDD) is the most potent Ah receptor agonist because of its high affinity to bind to the receptor and its resistance to metabolism. TCDD is known to have immunosuppressive effects particularly when exposure occurs during the fetal or neonatal periods. Although most cells of the immune system express the Ah receptor, Ah receptor knockout mice show no immune system defects. In wild-type mice, activation of the Ah receptor by TCDD leads to immune suppression, although the underlying cellular mechanisms are unknown.

Advance: Recent studies by this NIEHS-supported laboratory have shown expression of the Ah receptor in both cytotoxic and helper T cells is necessary for TCDD to completely suppress the T cell response in a graft vs. host model. Now this team has used the same model to show that activation of the Ah receptor in donor T cells leads to the production of a subpopulation of helper T cells that express high levels of specific surface antigens, namely CD25, CD62L^low, CTLA-4, and glucocorticoid-induced tumor necrosis factor receptor. Further analysis revealed that the CD4⁺ CD2⁺ cells demonstrate functional characteristics of regulatory T cells. It remains to be determined if Ah receptor ligands other than TCDD produce the same effect.

Implications: These findings represent a previously unidentified role for the Ah receptor in the generation of regulatory T cells and provide new perspectives on the mechanisms that underlie the profound immune suppression caused by exposure to TCDD. The results from this study provide insight into the role that this widely expressed receptor pathway may play in normal development and function of the immune system.

Citation: Funatake CJ, Marshall NB, Steppan LB, Mourich DV, Kerkvliet NI. Cutting edge: Activation of the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin generates a population of CD4+ CD25+ cells with characteristics of regulatory T cells. J Immunol. 2005 Oct 1;175(7): 4184-8.