T cell-derived IL-4 and dendritic cell-derived IL-12 regulate the lymphokine-producing phenotype of alloantigen-primed naive human CD4 T cells.
Previous studies on human Th subset development were restricted to the analysis of naive T cells activated with anti-CD3 mAb in the absence of physiologic APC. In this study, we have analyzed the role of cytokines and physiologic APC on T cell maturation in an Ag-specific system, in which naive neonatal CD4 T cells were primed with allogeneic dendritic cells (DC). We found that the cytokine profile of primed cells was dependent upon 1) the ratio between T cells and allogeneic DC and 2) the endogenous production of IL-4 and IL-12. Neutralization of IL-4 during primary MLR increased IFN-gamma production at priming and shifted the phenotype of primed cells from Th0 to Th1. These effects were IL-12 dependent, in that they were suppressed by anti-IL-12 Abs. The production of IL-12 in primary MLR was further evidenced by the presence of IL-12 p40 in the culture supernatant fluids. IL-12 production was suppressed by exogenous IL-4 and increased by anti-IL-4 blocking mAbs, indicating that endogenous IL-4 down-regulated IL-12 production by DC. Finally, IL-12 was produced as a result of T cell/DC interaction involving the CD40/CD40 ligand and CD28/B7 costimulation pathways, as revealed by the inhibitory effect of anti-CD40 ligand mAb and CTLA-4Ig. These observations suggest that in neutral conditions, Ag presentation by DC results in the coordinate production of naive T cell-derived IL-4 and DC-derived IL-12 that in concert shape the cytokine profile of Th cells.
Ohshima
Y
Y
University of Montreal, Louis-Charles Simard Research Center, Notre-Dame Hospital, Quebec, Canada.
Delespesse
G
G
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D007114:Immunization / Q000379:methods; D016130:Immunophenotyping / Q000379:methods; D007231:Infant, Newborn; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000494:pharmacology*; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000494:pharmacology*; D007519:Isoantigens / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008222:Lymphokines / Q000096:biosynthesis*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*
D007519:Isoantigens; D008222:Lymphokines; D018664:Interleukin-12; D015847:Interleukin-4