Nonhematopoietic antigen blocks memory programming of alloreactive [CD8.sup.+] T cells and drives their eventual exhaustion in mouse models of bone marrow transplantation

• Published in: The Journal of clinical investigation Vol. 120; no. 11; pp. 3855 - 3868
• Main Authors: Flutter, Barry, Edwards, Noha, Fallah-Arani, Farnaz, Henderson, Stephen, Chai, Jian-Guo, Sivakumaran, Shivajanani, Ghorashian, Sara, Bennett, Clare L, Freeman, Gordon J, Sykes, Megan, Chakraverty, Ronjon
• Format: Journal Article
• Language: English
• Published: American Society for Clinical Investigation 01.11.2010
• Subjects: Bone marrow; CD8 lymphocytes; Genetic aspects; Graft versus host reaction; Physiological aspects; Risk factors; Transplantation; United Kingdom
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI41446

Allogeneic blood or BM transplantation (BMT) is the most commonly applied form of adoptive cellular therapy for cancer. In this context, the ability of donor T cells to respond to recipient antigens is coopted to generate graft-versus-tumor (GVT) responses. The major reason for treatment failure is tumor recurrence, which is linked to the eventual loss of functional, host-specific CTLs. In this study, we have explored the role of recipient antigen expression by nonhematopoietic cells in the failure to sustain effective CTL immunity. Using clinically relevant models, we found that nonhematopoietic antigen severely disrupts the formation of donor [CD8.sup.+] T cell memory at 2 distinct levels that operate in the early and late phases of the response. First, initial and direct encounters between donor [CD8.sup.+] T cells and nonhematopoietic cells blocked the programming of memory precursors essential for establishing recall immunity. Second, surviving [CD8.sup.+] T cells became functionally exhausted with heightened expression of the coinhibitory receptor programmed death-1 (PD-1). These 2 factors acted together to induce even more profound failure in long-term immunosurveillance. Crucially, the functions of exhausted [CD8.sup.+] T cells could be partially restored by late in vivo blockade of the interaction between PD-1 and its ligand, PD-L1, without induction of graft-versus-host disease, suggestive of a potential clinical strategy to prevent or treat relapse following allogeneic BMT.