Fas-mediated lysis of chronic lymphocytic leukaemia cells: role of type I versus type II cytokines and autologous FasL-expressing T cells

Given the known role of the fas cytolytic pathway in B-cell regulation, we evaluated whether fas-fasL interactions might induce chronic lymphocytic le ukaemia (CLL) cell death. De novo CLL cells expressed a low level of surfac e fas, and were not lysed by fasL-bearing cells. CLL cells cultured in medi a containing the type I cytokines interleukin (IL)-12 or interferon (IFN)-a lpha had increased fas expression, and were readily lysed by fasL-bearing c ells. In contrast, the type II cytokine IL-4 did not increase CLL cell fas, and abrogated type I cytokine-induced fas up-regulation, With prolonged cu lture, IL-4 exposed CLL cells expressed an intermediate level of fas; howev er, such CLL cells were resistant to fas-mediated lysis. These results indi cate that IL-4 inhibits fas-mediated killing of CLL cells at the level of b oth fas receptor expression and post-receptor events. Additionally, we have defined in vitro culture conditions which generate fasL-bearing T cells fr om CLL patients; such T cells efficiently mediated fas-based lysis of autol ogous fas-positive CLL cells. We therefore conclude that type I and type II cytokines differentially regulate the fas pathway in CLL cells, and that a combination of type I cytokines and fasL-expressing T cells may represent a new approach to the immunotherapy of CLL.