title: Granzyme B Contributes to the Optimal Graft-Versus-Tumor Effect Mediated by Conventional CD4+T Cells.
abstract: Granzyme B (GzmB) is a key cytotoxic molecule utilized by T cells to kill pathogen-infected cells or transformed tumor cells. Previous studies using allogeneic hematopoietic cell transplantation (allo-HCT) murine models showed that GzmB is required for CD8+T cells to cause graft-versus-host disease (GVHD). However, our recent study demonstrated that GzmB-mediated damage of CD8+T cells diminished their graft-versus-tumor (GVT) activity. In this study, we examined the role of GzmB in GVT effect mediated by conventional CD4+CD25-T cells (CD4+Tcon). GzmB-/-CD4+Tcon cells exhibited decreased GVT activity compared to wild-type (WT) CD4+Tcon cells, suggesting that GzmB is required for the optimal GVT activity of CD4+Tcon cells. On the other hand, GzmB-/-CD4+CD25+regulatory T cells were as suppressive as WT regulatory T cells in suppressing GVT activity, which is consistent with our previous report showing that GzmB is not required for regulatory T cell-mediated suppression of GVHD. These results demonstrate that GzmB causes opposite impacts on GVT effect mediated by CD4+CD25-versus CD8+T cells. Interestingly, GzmB-/-total T cells exhibited GVT activity equivalent to that of WT total T cells, suggesting that the opposite impacts of GzmB on the GVT effect of CD4+CD25-versus CD8+T cells may neutralize each other, which can only be observed when an individual T cell subset is examined. Importantly, these differential roles suggest that targeting GzmB in selective T cell subsets may have the potential to enhance the beneficial GVT effect.
authors: Department of Immunology, Roswell Park Cancer Institute, Buffalo, USA.
authors: Wei
authors: W
authors: Du
authors: Department of Immunology, Roswell Park Cancer Institute, Buffalo, USA.
authors: Nicholas D
authors: ND
authors: Leigh
authors: Department of Immunology, Roswell Park Cancer Institute, Buffalo, USA.
authors: Guanglin
authors: G
authors: Bian
authors: Department of Immunology, Roswell Park Cancer Institute, Buffalo, USA.
authors: Emad
authors: E
authors: Alqassim
authors: Department of Immunology, Roswell Park Cancer Institute, Buffalo, USA.
authors: Rachel E
authors: RE
authors: O'Neill
authors: Department of Internal Medicine, University at Buffalo, Buffalo, USA.
authors: Lin
authors: L
authors: Mei
authors: Department of Pathology, Roswell Park Cancer Institute, Buffalo, USA.
authors: Jingxin
authors: J
authors: Qiu
authors: Department of Medicine, Roswell Park Cancer Institute, Buffalo, USA.
authors: Hong
authors: H
authors: Liu
authors: Department of Medicine, Roswell Park Cancer Institute, Buffalo, USA.
authors: Philip L
authors: PL
authors: McCarthy
authors: Department of Immunology, Roswell Park Cancer Institute, Buffalo, USA.
authors: Xuefang
authors: X
authors: Cao
keywords: Allogeneic hematopoietic cell transplantation (allo-HCT); Graft-versus-host-disease (GVHD); Graft-versus-tumor (GVT) effect; Granzyme B (GzmB); T cells