Low level lead exposure in vitro stimulates the proliferation and expansion of alloantigen-reactive CD4(high) T cells.
T cells are believed to be critical functional targets of Pb immunotoxicity. In this study, low concentrations of lead (i.e., as low as 0.1 microM approximately 2 microg/dl) were found to markedly enhance the allogeneic mixed lymphocyte reaction-an assay of CD4(+) T cell responsiveness. Cell cycle analysis of cells recovered from allogeneic mixed lymphocyte cultures revealed that Pb stimulated a substantial increase in the proportion of cycling alloreactive CD4(+) T cells. The enhanced alloproliferative response was characterized by an increased population of lymphoblasts expressing heightened cell surface expression of CD4 (i.e., CD4(high) cells). Successive rounds of cell division were monitored using the cell division dye 5- (and 6)-carboxyfluorecein diacetate succinimyl ester and it was determined that the CD4(high) subpopulation comprised the expanding alloreactive T cells, which ultimately took on the phenotype of memory/effector T cells (i.e., CD44(high), CD45RB(low), CD69(high), and CD162(high)). Enhancement of T cell proliferation by lead was selective for responsiveness to alloantigen, as lead had no effect on T cell proliferation induced by mitogens or superantigen, processes that unlike alloreactivity are not dependent on antigen presentation. Collectively, these data suggest that Pb enhances alloantigen-specific T cell proliferation through an indirect mechanism involving altered antigen processing/presentation, resulting in marked clonal expansion or repertoire expansion of alloreactive T cell clones. Consistent with this suggestion was the finding that a single exposure to Pb during alloantigen priming elicited a population of CD4(+) T cells that was hyperresponsive to further alloantigen stimulation and neither lead dependent nor lead responsive.
McCabe
M J
MJ
Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, New York 14642, USA.
Singh
K P
KP
Reiners
J J
JJ
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D016130:Immunophenotyping; D007519:Isoantigens / Q000276:immunology*; D007854:Lead / Q000276:immunology / Q000633:toxicity*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008815:Mice, Inbred Strains; D008934:Mitogens / Q000276:immunology / Q000494:pharmacology; D018089:Superantigens / Q000276:immunology / Q000494:pharmacology
D015703:Antigens, CD; D007519:Isoantigens; D008934:Mitogens; D018089:Superantigens; D007854:Lead