Year of Award


Document Type


Degree Type

Doctor of Philosophy (PhD)

Degree Name


Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

David M. Shepherd

Commitee Members

Kevan Roberts, Howard Beall, Keith Parker, Scott Wetzel, Paige B. Lawrence


Aryl hydrocarbon receptor, Dendritic cells, Immunity, T cells, Antigen presenting cells, TCDD ( dioxin)


University of Montana


TCDD (dioxin) causes immunosuppression via activation of the Aryl hydrocarbon receptor (AhR). Dendritic cells (DCs), the professional antigen-presenting cells in the immune system, are adversely affected by TCDD. However, limited information exists regarding the effects of AhR activation on DCs. We evaluated the consequences of AhR activation by TCDD on both steady-state and inflammatory DCs using in vivo and in vitro approaches, respectively. We hypothesized that AhR activation alters DC homeostasis and differentiation leading to generation of immunosuppression. C57Bl/6 mice gavaged with an immunosuppressive dose of TCDD (15 ug/kg) displayed decreased frequency and number of splenic CD11chigh DCs on day 7. Moreover, TCDD induced a selective loss of the CD11chighCD8á-33D1+ splenic DCs subset, specialized at activating CD4+ T cells, but not the regulatory CD11chighCD8á+DEC205+ splenic DCs. Additionally, TCDD increased the expression of CD86 and CD54, while decreasing the frequency of CD11a and MHC II on the splenic CD11chigh DCs. Although TCDD did not alter the number and frequency of CD11clow splenic DCs, it decreased their MHC II and CD11a expression. The loss of CD11chigh DC was independent of an apoptotic event but involved a CCR7-mediated migratory event. Popliteal and brachial lymph node (PBLNs) CD11c+ cells displayed elevated levels of MHC II and CD40, but not DC loss following TCDD exposure. To examine the effects of TCDD on inflammatory DCs, BMDCs were generated in the presence of GM-CSF and vehicle or TCDD. TCDD decreased CD11c expression but increased MHC II, CD86 and CD25 expression on these BMDCs. These effects were AhR-dependent but not exclusively DRE-mediated. Additionally, TCDD modulated antigen uptake and increased LPS- and CpG-induced IL-6 and TNF-á levels but decreased nitric oxide production by the BMDCs. TCDD downregulated LPS- and CpG-induced p65 levels and induced a trend towards upregulation of RelB levels in BMDCs. Despite the induction of suppressive mediators IDO1, IDO2 and TGFâ3, TCDD-BMDCs failed to suppress T cell activation in vivo or induce the generation of adaptive T-regs in vitro. Collectively, our data suggest that AhR activation disrupts DC homeostasis, modulates DC differentiation, TLR responsiveness and induces a regulatory phenotype, effects that may underlie TCDD-induced immunosuppression.



© Copyright 2009 Jaishree Bankoti