Interactions between CD4+ T cells and B cells are mediated by both soluble factors and cell surface molecules. The Ag-independent interaction between the CD40 ligand, expressed on activated T cells, and its CD40 receptor, expressed on B cells, enhances B cell proliferation in response to IL-4 stimulation. The expression of the CD40 ligand is induced on CD4+ T cells by stimulation with Ag-pulsed APC or mitogens. Here, we show that at least some IL-4-producing murine CD8+ T cell clones can be induced to express the CD40 ligand when stimulated with anti-CD3 mAb. Additionally, such activated CD8+ IL-4-producing clones potentiate the proliferative response of small resting B cells to IL-4 and induce Ig secretion by small resting B cells to IL-4 and IL-5. Proliferation of small resting B cells cultured with IL-4 in the presence of activated IL-4-producing CD8+ murine T cell clones appeared to be mediated by the expression of the CD40 ligand on the T cell because an anti-CD40 ligand mAb inhibited this proliferative response. A conventional murine CD8+ CTL clone, which did not produce IL-4 or express CD40 ligand upon activation, did not potentiate proliferation of small resting B cells exposed to IL-4. Thus, under some circumstances, CD8+ T cells that are able to express CD40 ligand may be able to provide B cell help.