2,3,7,8-Tetrachlorodibenzo-p-dioxin Enhances Negative Selection of T Cells in the Thymus but Allows Autoreactive T Cells to Escape Deletion and Migrate to the Periphery
Exposure to 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), an environmental pollutant, has been shown to cause thymic atrophy and apoptosis. However, whether TCDD alters the process of T-cell selection in the thymus is not clear. To this end, we investigated the effects of TCDD in the context of the...
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Veröffentlicht in: | Molecular pharmacology 2005-01, Vol.67 (1), p.327-335 |
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Zusammenfassung: | Exposure to 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), an environmental pollutant, has been shown to cause thymic atrophy and apoptosis. However, whether TCDD alters
the process of T-cell selection in the thymus is not clear. To this end, we investigated the effects of TCDD in the context
of the HY-T-cell receptor (TCR) transgenic (Tg) mouse model. We noted that negatively selecting male HY-TCR Tg mice were significantly
more sensitive to the thymotoxic effects of TCDD relative to positively selecting female HY-TCR Tg mice, including increased
reduction in cellularity and increased induction of apoptosis. TCDD exposure also altered the thymocyte subset composition
in HY-TCR Tg male but not female mice. In addition, TCDD treatment resulted in increased extracellularly regulated kinase
phosphorylation and lymphocyte-specific protein tyrosine kinase expression in thymocytes of HY-TCR Tg male but not female
mice. The increase in proportion of CD8 + mature thymocytes noted in HY-TCR Tg male mice was reflected in the periphery, with TCDD-exposed HY-TCR Tg male mice having
increased numbers of CD8 + T cells. Finally, we noted that the proliferative response of HY-TCR Tg male T cells to HY(self)-Ag was enhanced after exposure
to TCDD, whereas that of HY-TCR Tg female mice was decreased. Taken together, these data suggest that TCDD alters the process
of thymic selection, possibly by enhancing negative thymocyte selection, whereas at the same time allowing autoreactive T
cells to escape deletion in the thymus and immigrate to the periphery. |
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ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.104.005868 |