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. / Graduation date: 2006
| Identifer | oai:union.ndltd.org:ORGSU/oai:ir.library.oregonstate.edu:1957/28643 |
| Date | 01 May 2006 |
| Creators | Funatake, Castle J. |
| Contributors | Kerkvliet, Nancy I. |
| Source Sets | Oregon State University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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