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 leukaemia (CLL) cell death. De novo CLL cells expressed a low level of surface fas, and were not lysed by fasL-bearing cells. CLL cells cultured in media containing the type I cytokines interleukin (IL)-12 or interferon (IFN)-alpha had increased fas expression, and were readily lysed by fasL-bearing cells. 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 culture, IL-4 exposed CLL cells expressed an intermediate level of fas; however, such CLL cells were resistant to fas-mediated lysis. These results indicate that IL-4 inhibits fas-mediated killing of CLL cells at the level of both fas receptor expression and post-receptor events. Additionally, we have defined in vitro culture conditions which generate fasL-bearing T cells from CLL patients; such T cells efficiently mediated fas-based lysis of autologous 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.
Williams
J F
JF
Transplantation Therapy Section, Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Petrus
M J
MJ
Wright
J A
JA
Husebekk
A
A
Fellowes
V
V
Read
E J
EJ
Gress
R E
RE
Fowler
D H
DH
D017209:Apoptosis; D053222:Fas Ligand Protein; D006801:Humans; D007372:Interferons / Q000502:physiology*; D007378:Interleukins / Q000502:physiology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D013601:T-Lymphocytes / Q000473:pathology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007378:Interleukins; D008562:Membrane Glycoproteins; D019014:fas Receptor; D007372:Interferons