The influence of aryl hydrocarbon receptor activation on T cell fate Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/n009w449n

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  • 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds are well-recognized for their immunosuppressive activity, which is mediated through an intracellular receptor and transcription factor, aryl hydrocarbon receptor (AhR). Laboratory animals exposed to TCDD are less resistant to infection and have severely impaired humoral and cell-mediated immune responses. This dissertation addressed the hypothesis that exposure to TCDD disrupts early events during the activation of CD4⁺ T cells, leading to their premature loss from the spleen. Initially, ovalbumin (OVA)-specific CD4⁺ T cells from transgenic DO11.10 mice were used to monitor the effects of TCDD on activated antigen-specific T cells. A graft-versus-host (GVH) model, in which T cells from C57B1/6 (B6) mice are injected into C57B1/6 x DBA/2 Fl (Fl) mice, was used to study the role of AhR specifically in the T cells in response to TCDD. B6 donor T cells (from AhR[superscript +/+] or AhR[superscript -/-] mice) respond to DBA/2 antigens in Fl mice and a CD4-dependent CTL response is generated. In both models, exposure to TCDD significantly decreased the number of responding CD4⁺ T cells in the spleen beginning on day 4 after initiation of the response. Exposure to TCDD altered the phenotype of OVA-specific CD4⁺ T cells beginning on day 2 after immunization with OVA. These studies also suggested that apoptosis was not the primary mechanism responsible for the loss of CD4⁺ T cells from the spleen in TCDD-treated mice. Exposure to TCDD induced AhR-dependent changes in the phenotype of B6 donor CD4⁺ T cells such that a subpopulation of CD25⁺ cells was increased in TCDD-treated Fl mice, and these cells had in vitro functional characteristics consistent with regulatory T (Treg) cells. Exposure to TCDD increased the frequency of donor CD4⁺ T cells producing interleukin (IL)-2. In addition, increased expression of CD25 in TCDD-treated mice was correlated with increased signaling through the IL-2 receptor. However, IL-2 alone was not sufficient to mimic the potent immunosuppressive effects of TCDD. These results suggest that TCDD suppresses T cell immunity in part by inducing and/or expanding a subpopulation of Treg cells by a mechanism that may involve IL-2.
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