B-CELL-MEDIATED DOWN-REGULATION OF IFN-GAMMA AND IL-12 PRODUCTION INDUCED DURING ANTITUMOR IMMUNE-RESPONSES IN THE TUMOR-BEARING STATE

Unfractionated spleen cells taken from tumor-bearing mice contained tu mor-primed T cells which produced lymphokines such as IFN-gamma and IL -2 through collaboration with antigen-presenting cells (APC) binding t umor antigens when cultured in vitro, Here, we investigated the regula tory mechanisms underlying IFN-gamma production by T-APC interactions. Elimination of B cells from a splenic population of tumor-bearing mic e resulted in enhanced IFN-gamma production. Adding B cells back into cultures down-regulated IFN-gamma production to almost the same levels as those induced by unfractionated spleen cells. IL-2 production was not enhanced by a cell depletion, but rather was significantly suppres sed. IFN-gamma-selective up-regulation was due to an enhancement of IL -12 production because IL-12 was detected in B cell-depleted cultures and enhanced IFN-gamma production was prevented by addition of anti-IL -12 mAb or anti-CD40 ligand (CD40L) mAb capable of inhibiting CD40L-in duced IL-12 production. These results indicate that B cells interfere with IFN-gamma production induced through interactions between anti-tu mor T cells and APC, and this suppressive effect is based on the capac ity of CD40(+) B cells to down-regulate the CD40L-induced IL-12 produc tion by APC.