DIFFERENTIAL-EFFECTS OF LEAD AND CAMP ON DEVELOPMENT AND ACTIVITIES OF TH1-LYMPHOCYTES 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 d evelopment of Th2 cells and inhibiting the development of Th1 cells. W hen naive splenic CD4(+) T cells from DO11.10 ovalbumin-specific trans genic (OVA-tg) mice or OVA-tg/RAG2(-/-) mice were developed in vitro i n the presence of Pb, preferential skewing toward Th2 cells was eviden t. The Pb-driven skewing toward Th2 was blocked significantly in the p resence of exogenous IL-12 or anti-IL-4 mAbs. Although Pb and dibutyry l cAMP (dbcAMP) appear to have similar effects on the development and reactivity of Th1 cells, unlike Pb, dbcAMP did not enhance Th2 develop ment/activity. Further evidence of Pb's differential T cell effects wa s 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 o vercame Pb's inhibition of Th1 cells. Th1 cells treated with a phospho diesterase inhibitor had significantly elevated [cAMP](i) levels follo wing anti-CD3 activation in the presence of Pb, suggesting that Pb may inhibit Th1 development by enhancing adenylate cyclase activity and e levating the [cAMP], level. Similar to Pb, a low concentration (10 mu M) of dbcAMP inhibited IFN gamma production by Th1, which was prevente d by IL-12; however, inhibition of protein kinase A activity by KT5720 did not reverse these effects. These results indicate that the enviro nmental toxicant Pb can modify immune reactivities by significantly al tering the differentiation of precursor or naive Th cells as well as b y directly inhibiting Th1 cells and stimulating Th2 cells. (C) 1998 So ciety of Toxicology.