The immune system has been identified as a very sensitive target for the toxic effects of 2,3,7,S-tetrachlorodibenzo-p-dioxin (TCDD). Exposure to TCDD has been shown to disrupt the generation of both cell-mediated and humoral T cell-dependent immunity in laboratory animals; however, the mechanism remains unknown. In this dissertation, the hypothesis is tested that TCDD exposure alters T cell activation and differentiation either directly or by inhibiting the activation of antigen presenting cells (APC). Previous studies from our laboratory using the PSI5 tumor allograft model suggest that TCDD inhibited T cell activation by suppressing the induction of the costimulatory molecule CDS6 on B220+ and Mac-1+ cells. To address the effects of TCDD on APC, we further characterized the activation of splenic APC in the PSI5 model and found that TCDD suppressed the induction of the accessory molecules CDS6, CD54 and MHC II on APC as well as their production of IL-12. Although it was determined that the induction of these costimulatory molecules following PSI5 immunization was CD40independent, their in vivo expression could be enhanced by administering an agonistic antibody to CD40 to mice. APC from anti-CD40 treated mice expressed significantly higher levels of these accessory molecules and IL-12, and this enhanced APC activation was largely unaffected by TCDD. However, TCDD-treated mice receiving both P815 and
anti-CD40 were unable to generate T cell-dependent allograft immunity suggesting that suppression of APC activation may not be underlying TCDD immunosuppression. To address the direct effects of TCDD on T cell activation, we adoptively-transferred DO11.10 TCR transgenic T cells into syngeneic recipients and monitored their activation in vivo following exposure to antigen. Although treatment of adoptively-transferred mice had no effect on the expansion or activation of the OVA-specific CD4+ T cells, the production of
the T cell-derived cytokines IL-2, IFN-��, IL-4 and IL-10 was suppressed. These data
suggest that TCDD may suppress the differentiation of OVA-specific T cells into effector T helper cells which are capable of driving T cell-dependent immune responses. / Graduation date: 2000
| Identifer | oai:union.ndltd.org:ORGSU/oai:ir.library.oregonstate.edu:1957/33232 |
| Date | 28 July 1999 |
| Creators | Shepherd, David M. |
| Contributors | Kerkvliet, Nancy I. |
| Source Sets | Oregon State University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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