The expression of CTLA-4 (CD152) on the cell surface of B cells and its consequences for the humoral immune response in vivo are unknown. We investigated the expression of CTLA-4 mRNA and protein in B cells in T cell-independent or -dependent ways. B cells in the presence of Ag-stimulated Th2 cells expressed mRNA of CTLA-4 and up-regulated intracellular CTLA-4 protein. Using a liposome-enhanced staining technique, we show for the first time, that surface CTLA-4 protein is expressed by 11-15% of B cells in a T cell-dependent culture system. To dissect the role of CTLA-4 on B cells in vivo, we used bone marrow chimeric mice in which only B cells were CTLA-4 deficient. These mice showed that early B cell development and homeostasis is not influenced by CTLA-4 deficiency of B cells. Ag-specific responses after immunization of the chimeric mice revealed elevated levels of IgM Abs in mice deficient for B cell CTLA-4. We propose that CTLA-4 signals on B cells determine the early fate of B cells in thymus-dependent immune responses.