Bidirectional regulation of human B cell responses by CD40-CD40 ligand interactions

Positive and negative effects of CD40 ligation on human B cell function were suggested by the observation that mAb to CD40 ligand partially blocked the suppressive influences of anti-CD3-stimulated control CD4+ T cells, as well as the B cell stimulatory effects of anti-CD3 activated mitomycin C-treated CD4+ T cells. To examine the negative effects of CD40 ligation in greater detail, B cells were cultured with anti-CD3 activated mitomycin C-treated CD4+ T cells that expressed optimal levels of CD40 ligand; additional recombinant human CD40 ligand significantly suppressed Ig production, but not proliferation. In contrast, when B cells were stimulated with SAC (formalinized Cowan I strain Staphylococcus aureus) and IL-2 in the absence of T cells, small amounts of recombinant CD40 ligand-stimulated Ig production, whereas larger quantities directly suppressed Ig secretion. The suppressive action of CD40 ligation on Ig production was most apparent after initial B cell activation. Moreover, IgD-memory B cells were significantly more sensitive to inhibition by CD40 ligation than IgD+ naive B cells. Engagement of CD40 not only suppressed Ig secretion by IgD- memory B cells, but also expression of CD38. Finally, activated B cells acquired the capacity to down-regulate CD40 ligand expression by stimulated CD4+ T cells more effectively than resting B cells. These results indicate that during T cell-B cell collaboration, engagement of CD40 can influence Ig production both positively and negatively, depending on the density of CD40 ligand as well as the stage of B cell activation and differentiation.