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Granzyme B Contributes to the Optimal Graft-Versus-Tumor Effect Mediated by Conventional CD4+ T Cells

Du, Wei ; Leigh, Nicholas D LU orcid ; Bian, Guanglin ; Alqassim, Emad ; O'Neill, Rachel E ; Mei, Lin ; Qiu, Jingxin ; Liu, Hong ; McCarthy, Philip L and Cao, Xuefang (2016) In Journal of immunology research and therapy 1(1). p.22-28
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... (More)

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.

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author
; ; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of immunology research and therapy
volume
1
issue
1
pages
22 - 28
publisher
Hindawi Limited
external identifiers
  • pmid:27774524
ISSN
2472-727X
language
English
LU publication?
no
id
310f68b6-41a8-4a17-a156-d974ddd14bf9
date added to LUP
2020-04-28 00:11:20
date last changed
2020-04-28 14:11:39
@article{310f68b6-41a8-4a17-a156-d974ddd14bf9,
  abstract     = {{<p>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.</p>}},
  author       = {{Du, Wei and Leigh, Nicholas D and Bian, Guanglin and Alqassim, Emad and O'Neill, Rachel E and Mei, Lin and Qiu, Jingxin and Liu, Hong and McCarthy, Philip L and Cao, Xuefang}},
  issn         = {{2472-727X}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{1}},
  pages        = {{22--28}},
  publisher    = {{Hindawi Limited}},
  series       = {{Journal of immunology research and therapy}},
  title        = {{Granzyme B Contributes to the Optimal Graft-Versus-Tumor Effect Mediated by Conventional CD4+ T Cells}},
  url          = {{https://lup.lub.lu.se/search/files/78925314/2016_Du_JIRT.pdf}},
  volume       = {{1}},
  year         = {{2016}},
}