title: Lead enhances CD4+ T cell proliferation indirectly by targeting antigen presenting cells and modulating antigen-specific interactions.
abstract: Although Pb is a well-known immunotoxicant, its mechanism of action is not well understood. Low levels of Pb (approximately 1 microM) markedly enhance the proliferative T cell response in mixed lymphocyte culture (MLC), a process we have termed allo-enhancement. As Pb allo-enhancement occurs whether alloantigen presenting cells (APC) are derived from C57BL/6 or BALB.B10, the allo-reactive T cells involved are likely to be specific for peptide in the context of the IA(b) molecule as the IE molecule is null in H-2(b) mice. Analysis of T cell division in MLC with Pb treatment indicated that there was no significant difference between Pb and non-Pb-treated cultures until day 4 when the frequency of proliferating T cells was much greater than in non-treated cultures. Our data suggest that this increased proliferation is not coupled with increased IL-2 levels in the media as these were actually decreased with Pb treatment and that Pb-induced enhancement in the allo-proliferative response is only partially dependent upon IL-2. Pb allo-enhancement is abrogated when stimulating allo-APCs are paraformaldehyde-fixed, and T cell proliferation stimulated by concanavalin A is not enhanced with Pb treatment, suggesting that the APC is the proximate target of Pb in allo-MLC. Pb allo-enhancement does not occur when T cells respond to irradiated allo-B cells, alone; however, it is restored when syngeneic CD11c-enriched cells are added. Of the CD11c-enriched splenocytes, the fraction that is adherent after 24 h, consistent with macrophages, appears to be the cell type targeted by Pb. Using T cells from DO11.10 transgenic mice, we determined that the effect of Pb is centered around specific p:MHC interactions and that enhanced costimulation is an unlikely mechanism for Pb allo-enhancement.
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Farrer
authors.forename: Sara M
authors.initials: SM
authors.lastname: Hueber
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McCabe
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects* / Q000502:physiology; D039521:CD11c Antigen / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002450:Cell Communication / Q000187:drug effects*; D005260:Female; D007376:Interleukin-2 / Q000502:physiology; D007519:Isoantigens / Q000276:immunology*; D007854:Lead / Q000633:toxicity*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D039521:CD11c Antigen; D007376:Interleukin-2; D007519:Isoantigens; D007854:Lead