Gene expression alterations in immune system pathways in the thymus after exposure to immunosuppressive Chemicals

Abstract

Background: Dysregulation of positive and negative selection, antigen presentation, or apoptosis in the thymus can lead to immunosuppression or autoimmunity. Diethylstilbestrol (DES), dexamethasone (DEX), cyclophosphamide (CPS), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are immunosuppressive chemicals that induce similar immunotoxic effects in the thymus, however, the mechanism of toxicity is purported to be different for each compound. Objectives: We hypothesized that genomic analysis of thymus after chemical-induced atrophy would yield transcriptional profiles that suggest pathways of toxicity associated with reduced function. Methods: Female B6C3F1 mice were exposed to these immunosuppressive agents and changes in gene expression and immune cell subpopulations were evaluated. Results: All four chemicals induced thymic atrophy and changes in both the relative proportion and absolute number of CD3+, CD4+/CD8-, CD4-/CD8+, and CD4+/CD8+ thymocytes. The most significant impact of exposure to DEX, DES, and CPS was modulation of gene expression in the T-cell receptor (TCR) complex and TCR and CD28 signaling pathways; this could represent a common mechanism of action and play a pivotal role in lineage commitment and development of T cells. Up-regulation of genes associated with the antigen presentation and dendritic cell maturation pathways was the most distinctive effect of TCDD exposure. These elements, which were also up-regulated by DEX and DES, contribute to positive and negative selection. Conclusions: Genomic analysis revealed gene expression changes in several pathways that are commonly associated with xenobiotic-induced immune system perturbations, particularly those that contribute to the development and maturation of thymic T cells.