TY - JOUR T1 - Primary Peripheral T Cells Become Susceptible to 2,3,7,8-Tetrachlorodibenzo-<em>p</em>-Dioxin-Mediated Apoptosis in Vitro upon Activation and in the Presence of Dendritic Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1722 LP - 1735 DO - 10.1124/mol.107.043406 VL - 73 IS - 6 AU - Narendra P. Singh AU - Mitzi Nagarkatti AU - Prakash Nagarkatti Y1 - 2008/06/01 UR - http://molpharm.aspetjournals.org/content/73/6/1722.abstract N2 - Although the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on T cells in vivo have been well characterized, attempts to reproduce these findings in vitro have not been successful. In the current study, we examined whether activation or the presence of dendritic cells (DCs) would make primary naive T cells from C57BL/6 mice susceptible to TCDD-induced apoptosis in vitro. Although nonactivated primary T cells cultured with 10 to 1000 nM TCDD were relatively resistant to apoptosis, they became sensitive to apoptosis upon activation with concanavalin A (ConA). Moreover, ConA-activated T cells cultured in the presence of DCs showed highest levels of TCDD-induced apoptosis. Likewise, primary T cells from OT.II.2a mice cultured with specific ovalbumin peptide and syngeneic DCs showed higher levels of apoptosis compared with similar nonactivated T cells. T-cell activation led to up-regulation of aryl hydrocarbon receptor (AhR), Fas, and Fas-ligand (FasL) expression. In addition, DC maturation and culture with TCDD caused significant induction of FasL. TCDD-mediated apoptosis in activated peripheral T cells was AhR-dependent. Analysis of why nonactivated T cells are more resistant, whereas activated T cells are sensitive to TCDD-induced apoptosis revealed that TCDD treatment of activated but not nonactivated T cells led to down-regulation of cellular FLICE inhibitory protein (c-FLIP), an inhibitor of apoptosis. Moreover, down-regulation of c-FLIP using small interfering RNA in nonactivated T cells made them sensitive to TCDD-induced apoptosis. The current study demonstrates for the first time that TCDD can induce apoptosis in vitro in peripheral T cells upon activation and in the presence of DCs and that this may be mediated by down-regulation of c-FLIP. The American Society for Pharmacology and Experimental Therapeutics ER -