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Granzyme B-Mediated Activation-Induced Death of CD4+ T Cells Inhibits Murine Acute Graft-versus-Host Disease

Du, Wei ; Leigh, Nicholas D LU orcid ; Bian, Guanglin ; O'Neill, Rachel E ; Mei, Lin ; Qiu, Jingxin ; Chen, George L ; Hahn, Theresa ; Liu, Hong and McCarthy, Philip L , et al. (2015) In Journal of immunology 195(9). p.4514-4523
Abstract

Granzyme B (GzmB) has previously been shown to be critical for CD8(+) T cell-mediated graft-versus-host disease (GVHD) but dispensable for GVHD mediated by CD4(+) T cells. However, previous studies used high doses of CD4(+) T cells in MHC-mismatched models that caused rapid and lethal GVHD. Because of the hyperacute lethality, it is possible that the role of GzmB was concealed by the system. Therefore, in this study, we have titrated down the T cell dose to precisely determine the contribution of GzmB in GVHD mediated by CD4(+)CD25(-) T cells. Surprisingly, we have found that GzmB(-/-)CD4(+)CD25(-) T cells cause more severe GVHD compared with wild-type CD4(+)CD25(-) T cells in both MHC-matched and mismatched models. Mechanistic analyses... (More)

Granzyme B (GzmB) has previously been shown to be critical for CD8(+) T cell-mediated graft-versus-host disease (GVHD) but dispensable for GVHD mediated by CD4(+) T cells. However, previous studies used high doses of CD4(+) T cells in MHC-mismatched models that caused rapid and lethal GVHD. Because of the hyperacute lethality, it is possible that the role of GzmB was concealed by the system. Therefore, in this study, we have titrated down the T cell dose to precisely determine the contribution of GzmB in GVHD mediated by CD4(+)CD25(-) T cells. Surprisingly, we have found that GzmB(-/-)CD4(+)CD25(-) T cells cause more severe GVHD compared with wild-type CD4(+)CD25(-) T cells in both MHC-matched and mismatched models. Mechanistic analyses reveal that although GzmB does not affect donor T cell engraftment, proliferation or tissue-specific migration, GzmB(-/-) CD4(+)CD25(-) T cells exhibit significantly enhanced expansion because of GzmB-mediated activation-induced cell death of wild-type CD4(+)CD25(-) T cells. As a result of enhanced expansion, GzmB(-/-) T cells produced higher amounts of proinflammatory cytokines (e.g., TNF-α and IFN-γ) that may contribute to the exacerbated GVHD. These results reveal that GzmB diminishes the ability of CD4(+) T cells to cause acute GVHD, which contradicts its established role in CD8(+) T cells. The differential roles suggest that targeting GzmB in selected T cell subsets may provide a strategy to control GVHD.

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type
Contribution to journal
publication status
published
subject
keywords
Acute Disease, Animals, Bone Marrow Transplantation/adverse effects, CD4-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/immunology, Cell Death/genetics, Cell Movement/genetics, Cell Proliferation/genetics, Cytokines/immunology, Flow Cytometry, Gastrointestinal Tract/immunology, Graft vs Host Disease/etiology, Granzymes/deficiency, Histocompatibility/genetics, Inflammation Mediators/immunology, Lymphocyte Activation/immunology, Mice, 129 Strain, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Spleen/cytology
in
Journal of immunology
volume
195
issue
9
pages
4514 - 4523
publisher
American Association of Immunologists
external identifiers
  • pmid:26392464
  • scopus:84945130988
ISSN
1550-6606
DOI
10.4049/jimmunol.1500668
language
English
LU publication?
no
additional info
Copyright © 2015 by The American Association of Immunologists, Inc.
id
bd2945ce-7221-421f-8b4c-c25efeca0755
date added to LUP
2020-04-30 23:16:27
date last changed
2024-06-26 15:58:04
@article{bd2945ce-7221-421f-8b4c-c25efeca0755,
  abstract     = {{<p>Granzyme B (GzmB) has previously been shown to be critical for CD8(+) T cell-mediated graft-versus-host disease (GVHD) but dispensable for GVHD mediated by CD4(+) T cells. However, previous studies used high doses of CD4(+) T cells in MHC-mismatched models that caused rapid and lethal GVHD. Because of the hyperacute lethality, it is possible that the role of GzmB was concealed by the system. Therefore, in this study, we have titrated down the T cell dose to precisely determine the contribution of GzmB in GVHD mediated by CD4(+)CD25(-) T cells. Surprisingly, we have found that GzmB(-/-)CD4(+)CD25(-) T cells cause more severe GVHD compared with wild-type CD4(+)CD25(-) T cells in both MHC-matched and mismatched models. Mechanistic analyses reveal that although GzmB does not affect donor T cell engraftment, proliferation or tissue-specific migration, GzmB(-/-) CD4(+)CD25(-) T cells exhibit significantly enhanced expansion because of GzmB-mediated activation-induced cell death of wild-type CD4(+)CD25(-) T cells. As a result of enhanced expansion, GzmB(-/-) T cells produced higher amounts of proinflammatory cytokines (e.g., TNF-α and IFN-γ) that may contribute to the exacerbated GVHD. These results reveal that GzmB diminishes the ability of CD4(+) T cells to cause acute GVHD, which contradicts its established role in CD8(+) T cells. The differential roles suggest that targeting GzmB in selected T cell subsets may provide a strategy to control GVHD. </p>}},
  author       = {{Du, Wei and Leigh, Nicholas D and Bian, Guanglin and O'Neill, Rachel E and Mei, Lin and Qiu, Jingxin and Chen, George L and Hahn, Theresa and Liu, Hong and McCarthy, Philip L and Cao, Xuefang}},
  issn         = {{1550-6606}},
  keywords     = {{Acute Disease; Animals; Bone Marrow Transplantation/adverse effects; CD4-Positive T-Lymphocytes/immunology; CD8-Positive T-Lymphocytes/immunology; Cell Death/genetics; Cell Movement/genetics; Cell Proliferation/genetics; Cytokines/immunology; Flow Cytometry; Gastrointestinal Tract/immunology; Graft vs Host Disease/etiology; Granzymes/deficiency; Histocompatibility/genetics; Inflammation Mediators/immunology; Lymphocyte Activation/immunology; Mice, 129 Strain; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Spleen/cytology}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{9}},
  pages        = {{4514--4523}},
  publisher    = {{American Association of Immunologists}},
  series       = {{Journal of immunology}},
  title        = {{Granzyme B-Mediated Activation-Induced Death of CD4+ T Cells Inhibits Murine Acute Graft-versus-Host Disease}},
  url          = {{http://dx.doi.org/10.4049/jimmunol.1500668}},
  doi          = {{10.4049/jimmunol.1500668}},
  volume       = {{195}},
  year         = {{2015}},
}