Local immunoglobulin production has been implicated in the pathogenesis of lung allograft rejection. The role of varying classes of lung accessory cells in stimulating an immunoglobulin (Ig) response in this setting as well as cytokines necessary for Ig synthesis is unknown. The purpose of the current study was to compare the accessory cell capabilities of lung dendritic cells (DC), parenchymal macrophages (PM), and alveolar macrophages (AM) in the generation of a humoral response to alloantigen. Allogeneic AM induced a dose-dependent production of IgG from peripheral blood mononuclear cells. In contrast, allogeneic DC and PM were unable to induce IgG synthesis. The inability of DC to stimulate IgG synthesis was observed despite a potent induction of T-cell proliferation and interferon-gamma (IFN-gamma) production. Additionally, supernatants from DC cultures suppressed AM-induced IgG production, suggesting that a soluble inhibitor of IgG synthesis was produced by DC-stimulated lymphocytes. AM-induced IgG synthesis was predominantly the result of IgG1 and IgG2 production. Experiments with blocking antibodies to either IFN-gamma or interleukin-4 (IL-4) revealed that both IFN-gamma and IL-4 participated in IgG synthesis, while only IFN-gamma was required for IgG2 production. These data demonstrate a discordance between the ability of lung accessory cells to induce T-cell proliferation and IgG synthesis. Furthermore, these findings suggest that local induction of either IL-4 or IFN-gamma is involved in stimulation of an IgG response to lung alloantigen.