,, TCDD (dioxin) is an environmental contaminant that has given rise to major human health concerns. It belongs to the family ofhalogenated aromatic hydrocarbons (HAH) and is considered to be the most toxic chemical ever created. The immune system is highly susceptible to the toxic effects of TCDD with marked effect on thymus and T cells. Recent studies from our lab demonstrated for the first time that TCDD can induce apoptosis in thymocytes and T cells in vivo involving Fas-Fas ligand (FasL) interactions. We found that Fas- and FasL-deficient mice were more resistant to TCDD-mediated immunotoxicity when compared to the wild-type mice. Because human subjects with similar mutations in Fas and FasL have been identified, our results suggested differential responsiveness to dioxin-like toxicants in the human population to immunotoxicity. Fas-FasL interactions play a critical role in T cell maturation and differentiation. Thus, any interference in these interactions can lead to autoimmunity and altered immune response to infectious agents or cancer. Thus, in the current study, we will test the central hypothesis that TCDD perturbs the development oft cell repertoire by interfering with the Fas-FasL interactions in the thymus. To this end, we will pursue 5 specific aims:
In aim 1, we will test whether TCDD induces apoptosis in T cells of the thymus of C57BL/6 mice through death-receptor (Fas) or the mitochondrial pathway either independently or through cross-talk. Also, the possible role played by ER stress pathway, the third novel apoptotic pathway, will also be investigated.
In aim 2, we will investigate if the interaction between T cells and stromal cells involving Fas and its ligand is responsible in induction of apoptosis in T cells using adoptive transfer of hematopoietic stem cells.
In aim 3, promoter region of Fas and FasL genes will be analyzed to characterize the mechanism(s) through which TCDD induces the expression of Fas and FasL.
In aim 4, we will use fetal thymic organ cultures derived from Fas-deficient and FasL-defective mice to analyze the apoptotic pathways using cDNA arrays.
In aim 5, the effect of prenatal exposure to TCDD on positive and negative selection of T cells in the developing thymus will be studied using TCR transgenic mice. Together, the current study should provide novel information on how prenatal and postnatal exposure to TCDD would alter the T cell repertoire by interfering with the apoptotic pathways.
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