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Evidence for direct action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on thymic epithelium
Abstract:
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) acts on selected targets within the immune system to produce a characteristic profile of pathologic responses typified by thymic atrophy, suppressed cellular immunity, and inhibition of antibody production to T-lymphocyte-dependent antigens. Studies in inbred mice differing in sensitivity to TCDD indicate that TCDD-induced thymic atrophy is mediated by a receptor protein (designated the Ah receptor). To study the cellular and molecular basis for TCDD-induced thymic atrophy, primary cultures of thymic epithelial (TE) cells were established from C57BL/6 mice, a strain sensitive to TCDD. Treatment of TE monolayers with TCDD (0.1 to 10 nM) resulted in the altered maturation of cocultured syngeneic thymocytes as judged by suppression (40% of control at 10 nM TCDD) of TE-dependent responsiveness of thymocytes to the mitogens concanavalin A and phytohemagglutinin. TE-conditioned medium enhanced the mitogen responsiveness of thymocytes three- to four-fold; however, the enhanced mitogen response mediated by the TE-conditioned medium was not suppressed in thymocytes incubated in medium collected from TCDD-treated cultures or in TE-conditioned medium to which TCDD (10 nM) had been added directly. The suppression of TE-dependent maturation of thymocytes was concentration dependent (EC50 approximately 1 nM) and stereospecific, suggesting involvement of the Ah receptor. The Ah receptor in cytosol fractions from cultured TE cells was measured directly and was found to be present at a concentration 3 and 3.5 times greater than that measured in whole thymus and thymocytes, respectively. The results of this study indicate that TCDD can act directly on epithelial target cells in the thymus: one consequence of this action appears to be the altered thymus-dependent maturation of T-lymphocyte precursors, mediated through direct cell-cell contact between thymocytes and TE cells.
Insights
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) directly impacts thymic epithelial cells, altering T-lymphocyte maturation. This dioxin exposure suppresses immune responses by affecting thymocyte development through cell-to-cell contact, mediated by the Ah receptor.
Area of Science:
- Immunology
- Toxicology
- Cell Biology
Background:
- 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to suppress immune function, particularly thymic atrophy and reduced T-lymphocyte responses.
- The Ah receptor is implicated in mediating TCDD's toxic effects, including thymic atrophy.
Purpose of the Study:
- To investigate the cellular and molecular mechanisms underlying TCDD-induced thymic atrophy.
- To determine if thymic epithelial (TE) cells are direct targets of TCDD action.
- To elucidate the role of TE cells in TCDD's impact on thymocyte maturation.
Main Methods:
- Primary cultures of thymic epithelial (TE) cells were established from TCDD-sensitive C57BL/6 mice.
- TE cells were treated with varying concentrations of TCDD.
- Cocultures of TE cells and syngeneic thymocytes were used to assess thymocyte maturation.
- TE-conditioned medium was analyzed for its effect on thymocyte responsiveness.
- Ah receptor levels in TE cells were quantified.
Main Results:
- TCDD treatment of TE cells altered the maturation of cocultured thymocytes, suppressing their responsiveness to mitogens.
- TE-conditioned medium alone did not replicate the suppressive effects of TCDD.
- The suppression of thymocyte maturation was concentration-dependent and stereospecific, indicating Ah receptor involvement.
- Thymic epithelial cells exhibited higher concentrations of the Ah receptor compared to whole thymus or thymocytes.
Conclusions:
- TCDD directly acts on thymic epithelial cells.
- This direct action on TE cells leads to altered thymus-dependent maturation of T-lymphocyte precursors.
- The mechanism involves direct cell-cell contact between thymocytes and TE cells, mediated by the Ah receptor.