Previous studies in our laboratory have shown that altered T cell function in C57Bl/6 mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a primary mechanisms for the suppression of both humoral and cell-mediated immunity in TCDD-treated mice. Because the activation of different regulatory T cell subpopulations determined both the nature and magnitude of subsequent immune responses, we have examined the effect of TCDD on events associated with T cell activation. These studies have used an in vivo model of T cell activation induced by antibody to the T cell receptor (alphaCD3) in lymph node cells draining the site of alphaCD3 injection. The unexpected results of these studies have shown that TCDD dose-dependently enhanced T cell activation. Evidence for enhanced activation includes increased incorporation of 3H-TdR, increased percentage of CD4+ and CD8+ T cells in S/G2M, and increased proliferation response to exogenous IL-2. Because activation events are tightly regulated in relationship to differentiation, we believe that the changes induced by TCDD in T cell activation may underlie the suppression of immune function in TCDD-treated animals. For example, inappropriate activation of T helper subsets (TH1/TH2) can alter the lymphokine milieu, leading to suppressed immune responses. Alternatively, inappropriate activation of T suppressor cells could down modulate immune responses. Also it is possible TCDD delivers both activating and inhibitory signals to T cells, which could depend on the dose, time of exposure, stage of cell maturation, and/or other activation signals.
The specific aims of this grant application are to further characterize the enhanced T cell activation induced by TCDD and to relate the enhanced activation to suppression of antigen-specific immune responses. We will investigate the conditions under which TCDD exposure produces enhanced T cell activation and explore the potential biochemical and molecular mechanisms by which TCDD exposure results in enhanced T cell activation of specific T cell subsets. We will examine the influence of TCDD on CD3 receptor down modulation, IL-2 receptor expression, IL-2 production, and expression of other activation antigens (CD2, CD28, CD45, CD69) induced or modulated by CD3 receptor binding. Specific biochemical consequences of TCDD-T cell interactions related to signal transduction will be assessed by protein tyrosine kinase activities, phosphatidylinositol metabolism, Ca2+ levels, and oncogene expression. In collaboration with Dr. Arleen Rifkind, we will determine if TCDD alters arachidonic acid metabolism in T cells and/or macrophages. Finally, we will determine the relationship between TCDD effects on T cell activation and suppressed immune responsiveness to antigen challenge. Studies will examine the influence of TCDD exposure on the development of T helper function (lymphokine production) and cytotoxic T cell function following alphaCD3 or alloantigen stimulation. It is interesting to note that enhanced T cell proliferation has been reported in humans exposed to TCDD, which has been interpreted by some to suggest a lack of TCDD immunotoxicity in this species. However, our results clearly show that enhanced T cell proliferation may occur concomitantly with suppressed antigen-specific immune responses. Thus, understanding the basis for the enhanced T cell activation and proliferation and the relationship to suppressed immune function are the important goals of this grant.
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