CD4+ T cells kill Id+ B-lymphoma cells: FasLigand-Fas interaction is dominant in vitro but is redundant in vivo.
B-lymphoma cells express a highly tumor-specific antigen, monoclonal Ig, which is a promising target for immunotherapy. Previous work has demonstrated that B-lymphoma cells spontaneously process their endogenous monoclonal Ig and present variable (V) region peptides (Id-peptides) on their MHC class II molecules to CD4+ T cells. Id-specific CD4+ T cells protect mice against B-lymphoma cells in the absence of antiidiotypic antibodies. The molecular mechanism by which Id-specific CD4+ T cells kill B-lymphoma cells is hitherto unknown. We here demonstrate in an Id-specific T-cell receptor (TCR)-transgenic mouse model that Id-specific CD4+ T cells induce apoptosis of Fas+ B-lymphoma cells in vitro by FasLigand (FasL)-Fas interaction. Moreover, the rare B lymphomas that had escaped rejection in TCR-transgenic mice had down-regulated their sensitivity to Fas-mediated apoptosis. Although these results suggest that FasL-Fas interaction is important, Id-specific CD4+ T cells could eliminate Id+ B-lymphoma cells in vivo by other mechanisms, since three independent ways of blocking FasL-Fas-mediated killing failed to abrogate tumor protection in TCR-transgenic mice. These results suggest that there are several redundant pathways by which Id-specific CD4+ T cells eliminate Id+ B-lymphoma cells in vivo, of which FasL-Fas interaction is only one.
Lundin
Katrin U
KU
Institute of Immunology, University of Oslo, Rikshospitalet, N-0027 Oslo, Norway. k.u.lundin@labmed.uio.no
Screpanti
Valentina
V
Omholt
Hilde
H
Hofgaard
Peter O
PO
Yagita
Hideo
H
Grandien
Alf
A
Bogen
Bjarne
B
D000818:Animals; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D007130:Immunoglobulin Idiotypes / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D019014:fas Receptor / Q000502:physiology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007130:Immunoglobulin Idiotypes; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D007371:Interferon-gamma