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Gene expression alterations in immune system pathways in the thymus after exposure to immunosuppressive chemicals
Rachel Frawley1, Kimber White, Ronnetta Brown
1National Institute of Environmental Health Sciences, National Toxicology Program, Research Triangle Park, North Carolina, USA. frawleyr@niehs.nih.gov
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.
Insights
Chemicals like DES, DEX, CPS, and TCDD cause thymic atrophy and alter T-cell development. Genomic analysis reveals common and distinct pathways affected, impacting immune function and T-cell maturation.
Area of Science:
- Immunotoxicology
- Genomics
- T-cell development
Background:
- Dysregulation of thymic processes can lead to immune system disorders.
- Several chemicals, including Diethylstilbestrol (DES), dexamethasone (DEX), cyclophosphamide (CPS), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induce thymic atrophy through various mechanisms.
Purpose of the Study:
- To investigate the transcriptional profiles of the thymus following chemical-induced atrophy.
- To identify shared and distinct molecular pathways affected by different immunosuppressive agents.
Main Methods:
- Female B6C3F1 mice were exposed to DES, DEX, CPS, and TCDD.
- Gene expression and immune cell subpopulations within the thymus were analyzed.
Main Results:
- All four chemicals induced thymic atrophy and altered thymocyte populations (CD3+, CD4+/CD8-, CD4-/CD8+, CD4+/CD8+).
- DEX, DES, and CPS significantly modulated T-cell receptor (TCR) complex and signaling pathways, suggesting a common mechanism in T-cell development.
- TCDD uniquely upregulated genes in antigen presentation and dendritic cell maturation pathways, also influenced by DEX and DES, impacting thymic selection.
Conclusions:
- Genomic analysis identified gene expression changes in pathways related to xenobiotic-induced immune perturbations.
- These findings highlight critical pathways involved in thymic T-cell development and maturation affected by chemical exposure.
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