Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine that promotes IgA/IgG2b switching and secretion. Here, we show a differential effect of TGF-β1 on Ig production by lipopolysaccharide-stimulated spleen and lymph node (LN) B cells. Exogenous TGF-β1 increased IgA production in B cell cultures and IgG2b production by spleen B cells. In contrast, IgG2b was suppressed by TGF-β1 in cultures of LN B cells, although endogenous TGF-β was required for IgG2b production in LN B cell cultures. The suppressor properties of exogenous TGF-β1 (0.5 ng/ml) on IgG2b production by LN B cells were also seen when testing IgG1 or IgG2a induced by interleukin-4 or interferon-γ, respectively. These differences between B cells from each lymphoid tissue appeared to be related to a different TGF-β antiproliferative effect, since proliferation of LN B cells was extremely sensitive to TGF-β1 and IgG2b production was more sensitive than IgA to the TGF-β-mediated suppression. However, by counteracting the antiproliferative effect of TGF-β1 with a CD40 agonistic mAb (IC10), the IgG2b response by LN B cells was still lacking. IC10 was nevertheless inhibitory for IgG2b production in most cases, while increasing secretion of IgA in the very same cultures. Taken together, the results suggest that functional differences between spleen and LN B cells do exist, at least with regard to the immunomodulating properties of TGF-β on both proliferation and Ig production. Moreover, functional differences exist between cells committed for IgA and IgG2b regarding their sensitivity to the antiproliferative activity of TGF-β1 and the effect of CD40-derived signals on Ig secretion.