title: T cells require TRAIL for optimal graft-versus-tumor activity.
abstract: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that exhibits specific tumoricidal activity against a variety of tumors. It is expressed on different cells of the immune system and plays a role in natural killer cell-mediated tumor surveillance. In allogeneic hematopoietic-cell transplantation, the reactivity of the donor T cell against malignant cells is essential for the graft-versus-tumor (GVT) effect. Cytolytic activity of T cells is primarily mediated through the Fas-Fas ligand and perforin-granzyme pathways. However, T cells deficient for both Fas ligand and perforin can still exert GVT activity in vivo in mouse models. To uncover a potential role for TRAIL in donor T cell-mediated GVT activity, we compared donor T cells from TRAIL-deficient and wild-type mice in clinically relevant mouse bone-marrow transplantation models. We found that alloreactive T cells can express TRAIL, but the absence of TRAIL had no effect on their proliferative and cytokine response to alloantigens. TRAIL-deficient T cells showed significantly lower GVT activity than did TRAIL-expressing T cells, but no important differences in graft-versus-host disease, a major complication of allogeneic hematopoietic cell transplantation, were observed. These data suggest that strategies to enhance TRAIL-mediated GVT activity could decrease relapse rates of malignancies after hematopoietic cell transplantation without exacerbation of graft-versus-host disease.
authors.affiliation: Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Cornelius
authors.initials: C
authors.lastname: Schmaltz
authors.forename: Onder
authors.initials: O
authors.lastname: Alpdogan
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Kappel
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Muriglan
authors.forename: Jimmy A
authors.initials: JA
authors.lastname: Rotolo
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ongchin
authors.forename: Lucy M
authors.initials: LM
authors.lastname: Willis
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Greenberg
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Eng
authors.forename: James M
authors.initials: JM
authors.lastname: Crawford
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
authors.forename: Jacques J
authors.initials: JJ
authors.lastname: Peschon
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D006086:Graft vs Host Disease / Q000209:etiology; D020350:Graft vs Tumor Effect / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha