Lead enhances CD4 + T cell proliferation indirectly by targeting antigen presenting cells and modulating antigen-specific interactions

• Published in: Toxicology and applied pharmacology Vol. 207; no. 2; pp. 125 - 137
• Main Authors: Farrer, David G., Hueber, Sara M., McCabe, Michael J.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01.09.2005; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Alloantigen; Animals; Antigen presenting cells; Antigen-Presenting Cells - drug effects; Antigen-Presenting Cells - physiology; Biological and medical sciences; CD11c Antigen - analysis; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; Cell Communication - drug effects; CELL DIVISION; CELL PROLIFERATION; Chemical and industrial products toxicology. Toxic occupational diseases; CONCANAVALIN A; Female; HISTOCOMPATIBILITY COMPLEX; Immunotoxicity; Interleukin-2; Interleukin-2 - physiology; IRRADIATION; Isoantigens - immunology; LEAD; Lead - toxicity; Lymphocyte Activation - drug effects; LYMPHOCYTES; MACROPHAGES; Medical sciences; Metals and various inorganic compounds; Mice; Mice, Inbred BALB C; Pb allo-enhancement; PEPTIDES; RECEPTORS; Toxicology; TRANSGENIC MICE; TCR; BLL; Interleukin-2; MLC; Immunotoxicity; Transgenic mice; Antigen presenting cells; MHC; CLIP; Pb allo-enhancement; MIIC; Alloantigen; APC; Lead; p:MHC; Cell proliferation; Immunopathology; Targeting; Toxicity; Rodentia; Transgenic animal; Accessory cell; Heavy metal; Vertebrata; Target; Mammalia; Mouse; Antigen presenting cell; T-Lymphocyte; lnterleukin-2
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2004.12.017

Although Pb is a well-known immunotoxicant, its mechanism of action is not well understood. Low levels of Pb (∼1 μM) 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.