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Host-Derived CD70 Suppresses Murine Graft-versus-Host Disease by Limiting Donor T Cell Expansion and Effector Function

Leigh, Nicholas D LU orcid ; O'Neill, Rachel E ; Du, Wei ; Chen, Chuan ; Qiu, Jingxin ; Ashwell, Jonathan D ; McCarthy, Philip L ; Chen, George L and Cao, Xuefang (2017) In Journal of immunology 199(1). p.336-347
Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for hematologic and immunologic diseases. However, graft-versus-host disease (GVHD) may develop when donor-derived T cells recognize and damage genetically distinct normal host tissues. In addition to TCR signaling, costimulatory pathways are involved in T cell activation. CD27 is a TNFR family member expressed on T cells, and its ligand, CD70, is expressed on APCs. The CD27/CD70 costimulatory pathway was shown to be critical for T cell function and survival in viral infection models. However, the role of this pathway in allo-HCT is previously unknown. In this study, we have examined its contribution in GVHD pathogenesis. Surprisingly, Ab... (More)

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for hematologic and immunologic diseases. However, graft-versus-host disease (GVHD) may develop when donor-derived T cells recognize and damage genetically distinct normal host tissues. In addition to TCR signaling, costimulatory pathways are involved in T cell activation. CD27 is a TNFR family member expressed on T cells, and its ligand, CD70, is expressed on APCs. The CD27/CD70 costimulatory pathway was shown to be critical for T cell function and survival in viral infection models. However, the role of this pathway in allo-HCT is previously unknown. In this study, we have examined its contribution in GVHD pathogenesis. Surprisingly, Ab blockade of CD70 after allo-HCT significantly increases GVHD. Interestingly, whereas donor T cell- or bone marrow-derived CD70 plays no role in GVHD, host-derived CD70 inhibits GVHD as CD70-/- hosts show significantly increased GVHD. This is evidenced by reduced survival, more severe weight loss, and increased histopathologic damage compared with wild-type hosts. In addition, CD70-/- hosts have higher levels of proinflammatory cytokines TNF-α, IFN-γ, IL-2, and IL-17. Moreover, accumulation of donor CD4+ and CD8+ effector T cells is increased in CD70-/- versus wild-type hosts. Mechanistic analyses suggest that CD70 expressed by host hematopoietic cells is involved in the control of alloreactive T cell apoptosis and expansion. Together, our findings demonstrate that host CD70 serves as a unique negative regulator of allogeneic T cell response by contributing to donor T cell apoptosis and inhibiting expansion of donor effector T cells.

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author
; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Apoptosis, CD27 Ligand/deficiency, Gene Expression Regulation, Graft vs Host Disease/immunology, Interferon-gamma/immunology, Interleukin-17/immunology, Interleukin-2/immunology, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Spleen/cytology, T-Lymphocytes/immunology, Transplantation, Homologous, Tumor Necrosis Factor-alpha/immunology
in
Journal of immunology
volume
199
issue
1
pages
336 - 347
publisher
American Association of Immunologists
external identifiers
  • scopus:85021144475
  • pmid:28550198
ISSN
1550-6606
DOI
10.4049/jimmunol.1502181
language
English
LU publication?
no
additional info
Copyright © 2017 by The American Association of Immunologists, Inc.
id
89cdba3e-a965-4f18-a94d-881a09492501
date added to LUP
2020-04-27 23:57:56
date last changed
2022-09-09 19:41:15
@article{89cdba3e-a965-4f18-a94d-881a09492501,
  abstract     = {{<p>Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for hematologic and immunologic diseases. However, graft-versus-host disease (GVHD) may develop when donor-derived T cells recognize and damage genetically distinct normal host tissues. In addition to TCR signaling, costimulatory pathways are involved in T cell activation. CD27 is a TNFR family member expressed on T cells, and its ligand, CD70, is expressed on APCs. The CD27/CD70 costimulatory pathway was shown to be critical for T cell function and survival in viral infection models. However, the role of this pathway in allo-HCT is previously unknown. In this study, we have examined its contribution in GVHD pathogenesis. Surprisingly, Ab blockade of CD70 after allo-HCT significantly increases GVHD. Interestingly, whereas donor T cell- or bone marrow-derived CD70 plays no role in GVHD, host-derived CD70 inhibits GVHD as CD70-/- hosts show significantly increased GVHD. This is evidenced by reduced survival, more severe weight loss, and increased histopathologic damage compared with wild-type hosts. In addition, CD70-/- hosts have higher levels of proinflammatory cytokines TNF-α, IFN-γ, IL-2, and IL-17. Moreover, accumulation of donor CD4+ and CD8+ effector T cells is increased in CD70-/- versus wild-type hosts. Mechanistic analyses suggest that CD70 expressed by host hematopoietic cells is involved in the control of alloreactive T cell apoptosis and expansion. Together, our findings demonstrate that host CD70 serves as a unique negative regulator of allogeneic T cell response by contributing to donor T cell apoptosis and inhibiting expansion of donor effector T cells.</p>}},
  author       = {{Leigh, Nicholas D and O'Neill, Rachel E and Du, Wei and Chen, Chuan and Qiu, Jingxin and Ashwell, Jonathan D and McCarthy, Philip L and Chen, George L and Cao, Xuefang}},
  issn         = {{1550-6606}},
  keywords     = {{Animals; Apoptosis; CD27 Ligand/deficiency; Gene Expression Regulation; Graft vs Host Disease/immunology; Interferon-gamma/immunology; Interleukin-17/immunology; Interleukin-2/immunology; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Spleen/cytology; T-Lymphocytes/immunology; Transplantation, Homologous; Tumor Necrosis Factor-alpha/immunology}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{1}},
  pages        = {{336--347}},
  publisher    = {{American Association of Immunologists}},
  series       = {{Journal of immunology}},
  title        = {{Host-Derived CD70 Suppresses Murine Graft-versus-Host Disease by Limiting Donor T Cell Expansion and Effector Function}},
  url          = {{http://dx.doi.org/10.4049/jimmunol.1502181}},
  doi          = {{10.4049/jimmunol.1502181}},
  volume       = {{199}},
  year         = {{2017}},
}