T cells require TRAIL for optimal graft-versus-tumor activity

• Published in: Nature medicine Vol. 8; no. 12; pp. 1433 - 1437
• Main Authors: van den Brink, Marcel R.M, Schmaltz, Cornelius, Alpdogan, Onder, Kappel, Barry J, Muriglan, Stephanie J, Rotolo, Jimmy A, Ongchin, Jennifer, Willis, Lucy M, Greenberg, Andrew S, Eng, Jeffrey M, Crawford, James M, Murphy, George F, Yagita, Hideo, Walczak, Henning, Peschon, Jacques J
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.12.2002
• Subjects: Animals; Apoptosis Regulatory Proteins; Bone marrow; Graft vs Host Disease - etiology; Graft vs Tumor Effect - immunology; Hematopoietic Stem Cell Transplantation; Immune system; Membrane Glycoproteins - physiology; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; T-Lymphocytes - immunology; TNF-Related Apoptosis-Inducing Ligand; Transplantation; Transplantation, Homologous; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - physiology; Tumors
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm1202-797

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.