DIFFERENTIAL SENSITIVITY OF CD4(-LYMPHOCYTES TO THE KILLING EFFICACY OF FAS (APO-1() AND CD8(+) T)CD95) LIGAND(+) TUMOR-CELLS IN B-CHRONIC LYMPHOCYTIC-LEUKEMIA/

B-chronic lymphocytic leukemia (B-CLL) is characterized by cellular an d humoral immune defects resulting in increased rates of infection and disturbed immune surveillance against cancer cells as well as by the expansion of slowly proliferating tumor cells. We found increased Fas receptor (FasR) expression in peripheral blood CD4(+) and CD8(+) cells of B-CLL patients compared with the equivalent cells of healthy donor s. Although increased Fas receptor expression was significant in both T-lymphocytic subsets, only CD4(+) cells from B-CLL patients underwent apoptosis after treatment with the agonistic Fas antibody CH11. In CD 4(+) cells of B-CLL patients, the Fas-sensitivity also correlated with a CD4(+)/CD8(+) ratio below the lower threshold of healthy individual s (<1.0). By contrast, FasR expression in the CD19(+) fraction of B-CL L patients was downregulated compared with normal controls, and this w as associated with an insensitivity to CH11-induced apoptosis. The B-C LL cell line EHEB as well as CD19(+) cells from B-CLL patients constit utively expressed Fas ligand (FasL). The FasL was functionally active, as the B-CLL cell line as well as T-cell-depleted CD19(+) B-CLL fract ions were able to kill target T-acute lymphatic leukemia (T-ALL) cells in vitro. This effect was inhibited by the antagonistic FasR-antibody ZB4, the neutralizing anti-FasL monoclonal antibody (MoAb) NOK-2 or b y transfection of the caspase inhibitor crmA. These data point to the fact that expression of FasL on CD19(+) B-CLL cells, together with enh anced susceptibility of CD4(+) T cells toward FasL-bearing effector ce lls, are causally linked to the relative reduction of CD4(+) cells occ urring during B-CLL progression. These findings could explain the inve rsion of the ratio of CD4(+)/CD8(+) cell numbers, which may be causall y linked to the immune deficiency observed in these patients and to th e expansion of the neoplastic clone in B-CLL. (C) 1998 by The American Society of Hematology.