Year of Award
Doctor of Philosophy (PhD)
Department or School/College
Department of Biomedical and Pharmaceutical Sciences
David M. Shepherd
Howard Beall, Kevan Roberts, Erica Woodahl, Scott Wetzel, Terrance Kavanagh
2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), Aryl Hydrocarbon Receptor (AhR), CD4 T cells, Dendritic Cells, Immunology, Toxicology
University of Montana
The aryl hydrocarbon receptor (AhR) is a steroid-like transcription factor that mediates the toxicity of various environmental pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and TCDD-like compounds. Exposure to environmentally relevant levels of TCDD and TCDD congeners has been shown to cause immune suppression, yet the mechanisms underlying TCDD-induced immune suppression remain poorly understood. Dendritic cells (DCs) are professional antigen presenting cells (APCs) that play an integral role in both innate and adaptive immune responses. DCs constitutively express AhR and represent a highly sensitive immune cell population to AhR activation by environmental pollutants. In a murine inflammatory bone marrow-derived DC (BMDC) model, AhR activation has been shown to alter surface molecule expression and induce immnuoregulatory genes. To further these studies, we examined AhR activation in murine steady-state BMDCs, DCs that in vitro closely resemble DCs found in peripheral immune tissues in vivo. We found that similar to inflammatory BMDCs, TCDD-induced AhR activation disrupts steady-state BMDC differentiation, responsiveness to innate danger signals, and induces immunoregulatory gene expression. AhR activation has been implicated in the polarization of regulatory T cells (Tregs), which are capable of inhibiting immune responses and may contribute to the observed immune suppression following exposure to TCDD. Because both inflammatory and steady-state BMDCs upregulated immunoregulatory gene expression in response to TCDD, their potential to suppress CD4+ T cells responses was examined in antigen-specific DC:CD4+ T cell co-cultures in vitro. Both inflammatory and steady-state AhR activated BMDCs altered antigen-specific CD4+ T cell responses and induced Foxp3+ Tregs when compared to vehicle-treated BMDCs. These in vitro studies were followed by a series of in vivo studies, in which we demonstrated that TCDD-exposed mice immunized with antigen-laden BMDCs, or antigen with adjuvant generated an increased frequency of Foxp3+ Tregs and subsequently dampened antigen-specific CD4+ effector T cell responses. Furthermore, DCs from TCDD-treated mice displayed increased expression of immunoregulatory genes, suggesting that they may be contributing to deficient CD4+ effector T cells responses and the generation of Tregs as observed in our in vitro studies. Overall, these studies significantly advance our understanding of how AhR activation by TCDD and TCDD-like chemicals induces immune suppression.
Simones, Thomas, "CONSEQUENCES OF ARYL HYDROCARBON RECEPTOR ACTIVATION IN STEADY-STATE AND INFLAMMATORY DENDRITIC CELLS" (2012). Graduate Student Theses, Dissertations, & Professional Papers. 236.
© Copyright 2012 Thomas Simones