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 G2M. 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.
Neumann
C M
CM
College of Veterinary Medicine, Oregon State University, Corvallis 97331.
Oughton
J A
JA
Kerkvliet
N I
NI
D000818:Animals; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D005260:Female; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D000072317:Polychlorinated Dibenzodioxins; D015375:Receptors, Interleukin-2; D004247:DNA; D013936:Thymidine