BIDIRECTIONAL REGULATION OF HUMAN B-CELL RESPONSES BY CD40-CD40 LIGAND INTERACTIONS

Positive and negative effects of CD40 ligation on human B cell functio n 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 acti vated mitomycin C-treated CD4(+) T cells. To examine the negative effe cts of CD40 ligation in greater detail, B cells were cultured with ant i-CD3 activated mitomycin C-treated CD4(+) T cells that expressed opti mal levels of CD40 ligand; additional recombinant human CD40 ligand si gnificantly suppressed Ig production, but not proliferation, In contra st, when B cells were stimulated with SAC (formalinized Cowan I strain Staphylococcus aureus) and IL-2 in the absence of T cells, small amou nts of recombinant CD40 ligand-stimulated Ig production, whereas large r quantities directly suppressed Ig secretion, The suppressive action of CD40 ligation on Ig production was most apparent after initial B ce ll activation, Moreover, IgD(-) memory B cells were significantly more sensitive to inhibition by CD40 ligation than IgD(+) naive B cells. E ngagement of CD40 not only suppressed Ig secretion by IgD(-) memory B cells, but also expression of CD38. Finally, activated B cells acquire d the capacity to down-regulate CD40 ligand expression by stimulated C D4(+) T cells more effectively than resting B cells. These results ind icate that during T cell-B cell collaboration, engagement of CD40 can influence Ig production both positively and negatively, depending on t he density of CD40 ligand as well as the stage of B cell activation an d differentiation.