Differential effects of lead and cAMP on development and activities of Th1- and Th2-lymphocytes

Lead (Pb) is known to have detrimental effects on the central nervous, hematopoietic, renal, and immune systems. Herein, it is demonstrated that Pb can skew T cell reactivities by preferentially enhancing the development of Th2 cells and inhibiting the development of Th1 cells. When naive splenic CD4+ T cells from DO11.10 ovalbumin-specific transgenic (OVA-tg) mice or OVA-tg/RAG2-/- mice were developed in vitro in the presence of Pb, preferential skewing toward Th2 cells was evident. The Pb-driven skewing toward Th2 was blocked significantly in the presence of exogenous IL-12 or anti-IL-4 mAbs. Although Pb and dibutyryl cAMP (dbcAMP) appear to have similar effects on the development and reactivity of Th1 cells, unlike Pb, dbcAMP did not enhance Th2 development/activity. Further evidence of Pb's differential T cell effects was observed, in that regardless of the activation stimuli (Ag/APC; anti-CD3; PMA + ionomycin), the addition of PbCl2 consistently resulted in significant inhibition of IFN gamma production by a Th1 clone and in increased IL-4 production by a Th2 clone. In vitro addition of IL-12 overcame Pb's inhibition of Th1 cells. Th1 cells treated with a phosphodiesterase inhibitor had significantly elevated [cAMP]i levels following anti-CD3 activation in the presence of Pb, suggesting that Pb may inhibit Th1 development by enhancing adenylate cyclase activity and elevating the [cAMP]i level. Similar to Pb, a low concentration (10 microM) of dbcAMP inhibited IFN gamma production by Th1, which was prevented by IL-12; however, inhibition of protein kinase A activity by KT5720 did not reverse these effects. These results indicate that the environmental toxicant Pb can modify immune reactivities by significantly altering the differentiation of precursor or naive Th cells as well as by directly inhibiting Th1 cells and stimulating Th2 cells.