An IgGl mAb 1G10 derived from an autoimmuneMRL/Mp-Ipr/Ipr (MRL/Ipr)mouse has previously been shown to induce IL-3, TNF-αand IL-6 production, and autocrine growth in an IL-3-dependent myeloid cell line, FDC-P2/185-4. In the present study, we have attempted to further define the molecular mechanism responsible for the IG10-induced activation of FDC-P2/185-4 cells. We have shown that 1G10 lacked anti-IgG1 rheumatoid factor activity, failing to generate self-associated immune complexes. Since 1G10 stimulated cells in an FcγR-dependent manner, it seems likely that cross-linking of a cell surface antigen and FcyR by 1G10 antibody is responsible for the stimulation of FDC-P2/185-4 cells. Among several mAb specific to surface antigens expressed on FDC-P2/185-4 cells (MHC class I, LFA-1, and FcγR), only a mAb specific to theáchain of LFA-la was able to induce the IL-3 and FcγR-dependent proliferation of FDC-P2/185-4 cells, similar to that induced by 1G10. Immunoprecipitation analysis revealed that 1G10 recognized a polypeptide with a molecular mass of 140 kilodaltons (pi40), which differed from FcγR and from LFA-láchain. These results suggest that cross-linking of not general but particular cell surface antigens and FcyR stimulates FDC-P2/185-4 cells to produce cytokines resulting in their proliferation.