Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect.
In allogeneic bone marrow transplantation (BMT) donor T cells are primarily responsible for antihost activity, resulting in graft-versus-host disease (GVHD), and for antileukemia activity, resulting in the graft-versus-leukemia (GVL) effect. The relative contributions of the Fas ligand (FasL) and perforin cytotoxic pathways in GVHD and GVL activity were studied by using FasL-defective or perforin-deficient donor T cells in murine parent --> F1 models for allogeneic bone marrow transplantation. It was found that FasL-defective B6.gld donor T cells display diminished GVHD activity but have intact GVL activity. In contrast, perforin-deficient B6.pfp(-/-) donor T cells have intact GVHD activity but display diminished GVL activity. Splenic T cells from recipients of B6.gld or B6.pfp(-/-) T cells had identical proliferative and cytokine responses to host antigens; however, splenic T cells from recipients of B6.pfp(-/-) T cells had no cytolytic activity against leukemia cells in a cytotoxicity assay. In experiments with selected CD4(+) or CD8(+) donor T cells, the FasL pathway was important for GVHD activity by both CD4(+) and CD8(+) T cells, whereas the perforin pathway was required for CD8-mediated GVL activity. These data demonstrate in a murine model for allogeneic bone marrow transplantation that donor T cells mediate GVHD activity primarily through the FasL effector pathway and GVL activity through the perforin pathway. This suggests that donor T cells make differential use of cytolytic pathways and that the specific blockade of one cytotoxic pathway may be used to prevent GVHD without interfering with GVL activity.
Schmaltz
C
C
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Alpdogan
O
O
Horndasch
K J
KJ
Muriglan
S J
SJ
Kappel
B J
BJ
Teshima
T
T
Ferrara
J L
JL
Burakoff
S J
SJ
van den Brink
M R
MR
D000818:Animals; D016026:Bone Marrow Transplantation; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013601:T-Lymphocytes / Q000276:immunology*; D014181:Transplantation Immunology; D014184:Transplantation, Homologous
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin