We have previously reported CD4 expression in CD34+ hematopoietic progenitor cells and suggested a role of CD4 in normal hematopoiesis and its possible relationship with the pathogenesis of acquired immunodeficiency syndrome (AIDS). To investigate whether CD4 expression in bone marrow progenitor cells can explain bone marrow suppression in AIDS, monoclonal antibodies (mAbs) against human CD4 were developed by immunizing Balb/c mice with human thymocytes. Three mAbs completely blocked the binding of Leu3a antibody, a well-known anti-CD4 mAb, to thymocytes, which indicates overlap between the epitopes recognized by these and Leu3a antibodies. Interestingly, one of these mAbs, YG23, significantly inhibited colony formation of human bone marrow progenitor cells treated with GM-CSF. This is the first demonstration that ligation of CD4 by an anti-CD4 mAb suppresses GM-CSF mediated proliferation and differentiation of human hematopoietic progenitor cells by modifying the intracellular signaling pathway through CD4 molecules. Based on these findings, we propose that alteration of CD4 signaling by either cross-linked gp120 or antibodies directed against a certain epitope shared with the YG23 binding site of the CD4 molecule may play a role in bone marrow dysfunction in AIDS patients.