Differential Sensitivity of CD41 and CD81 T Lymphocytes to the Killing Efficacy of Fas (Apo-1/CD95) Ligand1 Tumor Cells in B Chronic Lymphocytic Leukemia

B-chronic lymphocytic leukemia (B-CLL) is characterized by cellular and 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 CD41 and CD81 cells of B-CLL patients compared with the equivalent cells of healthy donors. Although increased Fas receptor expression was significant in both T-lymphocytic subsets, only CD41 cells from B-CLL patients underwent apoptosis after treatment with the agonistic Fas antibody CH11. In CD41 cells of B-CLL patients, the Fas-sensitivity also correlated with a CD41/ CD81 ratio below the lower threshold of healthy individuals (F1.0). By contrast, FasR expression in the CD191 fraction of B-CLL patients was downregulated compared with normal controls, and this was associated with an insensitivity to CH11-induced apoptosis. The B-CLL cell line EHEB as well as CD191 cells from B-CLL patients constitutively expressed Fas ligand (FasL). The FasL was functionally active, as the B-CLL cell line as well as T-cell–depleted CD191 B-CLL fractions 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 by transfection of the caspase inhibitor crmA. These data point to the fact that expression of FasL on CD191 B-CLL cells, together with enhanced susceptibility of CD41 T cells toward FasL-bearing effector cells, are causally linked to the relative reduction of CD41 cells occurring during B-CLL progression. These findings could explain the inversion of the ratio of CD41/CD81 cell numbers, which may be causally linked to the immune deficiency observed in these patients and to the expansion of the neoplastic clone in B-CLL. r 1998 by The American Society of Hematology.