| First Author | Bian G | Year | 2013 |
| Journal | J Immunol | Volume | 190 |
| Issue | 3 | Pages | 1341-50 |
| PubMed ID | 23264653 | Mgi Jnum | J:192609 |
| Mgi Id | MGI:5465489 | Doi | 10.4049/jimmunol.1201554 |
| Citation | Bian G, et al. (2013) Granzyme B-Mediated Damage of CD8+ T Cells Impairs Graft-versus-Tumor Effect. J Immunol 190(3):1341-50 |
| abstractText | Allogeneic hematopoietic cell transplantation is an established treatment for hematologic and other malignancies. Donor-derived immune cells can identify and attack host tumor cells, producing a graft-versus-tumor (GVT) effect that is crucial to the treatment. Using multiple tumor models and diverse donor-host combinations, we have studied the role of granzyme B (GzmB) in GVT effect. We first confirmed previous findings that GzmB deficiency diminished the ability of a high dose of CD8(+) T cells to cause lethal graft-versus-host disease. However, when GVT studies were performed using a moderate cell dose that the hosts could tolerate, GzmB(-/-) CD8(+) T cells demonstrated a significantly enhanced GVT effect. GzmB-mediated, activation-induced cell death in wild-type CD8(+) T cells was found responsible for their reduced GVT activity. Conversely, GzmB(-/-) CD8(+) T cells exhibited enhanced expansion, skewed toward an effector or effector memory phenotype, and produced higher amounts of IFN-gamma and Fas ligand that might contribute to GzmB-independent tumor control. These findings demonstrate for the first time, to our knowledge, that GzmB-mediated damage of CD8(+) T cells impairs the desired GVT effect. This study suggests that inhibiting donor-derived GzmB function may represent a promising strategy to improve GVT effect without exacerbating graft-versus-host disease. |
