The effect of metals on IL-2-related lymphocyte proliferation

The heavy metals Pb, Ni and Zn have previously been demonstrated to stimulate the proliferation of an Lyt1+2-, L3T4+T-cell. This proliferation required the presence of Ia+ cells and was blocked by monoclonal antibodies directed against self I-A, self I-E and L3T4a. The work reported here examined the role of T-cell factors (IL-2 and gamma-IFN) and their receptors in the metal-induced lymphoproliferation. The metals Pb, Ni and Zn, at concentrations (100 microM) which stimulate T-cell proliferation, had little effect on the ability of the IL-2-dependent cell line HT-2 to respond to exogenous IL-2. This suggests that Pb, Ni and Zn do not modulate the ability of IL-2 to interact with the IL-2 receptor. Ni and Zn significantly enhanced the synthesis/secretion of IL-2 by cultured splenocytes and the expression of the receptor for IL-2; however, Pb produced only slight enhancement. Likewise, anti-IL-2 receptor (7D4) antibodies were able to inhibit a significant portion of the Ni- and Zn-, but not Pb-, induced lymphoproliferation. The residual 3H-thymidine incorporation observed in the presence of anti-IL-2 and anti-IL-2R may represent cycling B-cells induced to proliferate by activated, but non-cyclin, T-cells. Monoclonal anti-gamma-IFN (R4/6A2) equally inhibited all metal-induced lymphoproliferation, suggesting that metal-induced lymphoproliferation is dependent on the induction of gamma-IFN as well as IL-2 synthesis. The Pb-induced response being the least dependent on IL-2 lends support to the hypothesis that Pb, Ni and Zn may activate T-cells and/or B-cells by different mechanisms.