Anti-CD3-induced T-cell activation — II. Effect of 2,3,7,8- Tetrachlorodibenzo- p-Dioxin (TCDD)

An in vivo model was used to examine the effect of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) on various parameters of T-cell activation. In this model, the hamster anti-mouse monoclonal antibody 145-2C11 (anti-CD3) to the CD3 portion of the murine T-cell receptor was injected into both rear footpads of female C57B1/6 mice and the draining popliteal and inguinal lymph node cells (LNC) were removed 24 h later. Cyclosporin A (CsA) was included as a known immunosuppressive control. As expected, CsA (50 mg/kg, i.p.) suppressed anti-CD3-induced proliferation, IL-2-driven 3H-TdR incorporation, and IL-2R expression. In contrast, TCDD unexpectedly enhanced anti-CD3-induced 3H-TdR incorporation. Flow cytometric analysis showed that TCDD treatment increased the percentage of both CD4 + and CD8 + cells cycling in S and G 2M. LNC from TCDD-treated mice also had enhanced 3H-TdR incorporation when cultured in the presence of a saturating amount of exogenous mIL-2. TCDD did not significantly alter the percent positive or the number of IL-2 receptors (IL-2R) on either CD4 + or CD8 + cells when examined at several time points after anti-CD3 treatment. Both the kinetics and extent of anti-CD3-induced down-modulation of CD3 expression on CD4 + and CD8 + cells was unaffected by TCDD. TCDD alone did not result in enhanced 3H-TdR incorporation, cell cycling or IL-2R expression. Therefore, TCDD appears to be targeting T-cells that are undergoing activation rather than resting cells. The strength of the anti-CD3 model is evidenced by the fact that two known immunosuppressive compounds (CsA and TCDD) have distinct and opposite effects on T-cell activation. These findings suggest that the mechanism(s) by which CsA and TCDD impair T-cell function are different.