CD28 down-regulation on CD4 T cells is a marker for graft dysfunction in lung transplant recipients

Sean M. Studer, M. Patricia George, Xuehai Zhu, Yifang Song, Vincent G. Valentine, Michael W. Stoner, Jigme Sethi, Chad Steele, Steven R. Duncan

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Rationale: Repeated antigen-driven proliferations cause CD28 on T cells to down-regulate. We hypothesized that alloantigen-induced proliferations could cause CD28 down-regulation in lung transplant recipients. Objectives: To ascertain if CD28 down-regulation on CD4 T cells associated with manifestations of allograft dysfunction in lung transplant recipients. Methods: Peripheral blood CD4 T cells from 65 recipients were analyzed by flow cytometry, cytokine multiplex and proliferative assays, and correlated with clinical events. Measurements and Main Results: Findings that CD28 was present on less than 90% of total CD4 T cells were predominantly seen among the recipients with bronchiolitis obliterans syndrome (specificity = 88%). Perforin and granzyme B were produced by >50% of the CD4+CD28null cells, but less than 6% of autologous CD4+CD28+ cells (P < 0.006). CD4+CD28null cells also had increased productions of proinflammatory cytokines, but less frequently expressed regulatory T-cell marker FoxP3 (2.1 ± 1.3%), compared with autologous CD4 +CD28+ (9.5 ± 1.4; P = 0.01). Cyclosporine A (100 ng/ml) inhibited proliferation of CD4+CD28null cells by 33 ± 11% versus 68 ± 12% inhibition of CD4+CD28 + (P = 0.025). FEV1 fell 6 months later (0.35±0.04L) in recipients with CD4+CD28+/CD4 total less than 90% (CD28% Low) compared with 0.08 ± 0.08 L among CD4+CD28+/CD4total (CD28% High) greater than 90% (CD28% High) recipients (P = 0.013). Two-year freedom from death or retransplantation in CD28% Low recipients was 32 ± 10% versus 78 ± 6% among the CD28% High subjects (P < 0.0001). Conclusions: CD28 down-regulation on CD4 cells is associated with bronchiolitis obliterans syndrome and poor outcomes in lung transplantation recipients. CD4 +CD28null cells have unusual, potentially pathogenic characteristics, and could be important in the progression of allograft dysfunction. These findings may illuminate a novel paradigm of transplantation immunopathogenesis, and suggest that CD28 measurements could identify recipients at risk for clinical deteriorations.

Original languageEnglish (US)
Pages (from-to)765-773
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume178
Issue number7
DOIs
StatePublished - Oct 1 2008

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Down-Regulation
T-Lymphocytes
Transplants
Lung
Bronchiolitis Obliterans
Allografts
Cytokines
Isoantigens
Lung Transplantation
Regulatory T-Lymphocytes
Cyclosporine
Transplant Recipients
Flow Cytometry
Transplantation
Antigens

Keywords

  • Bronchiolitis obliterans syndrome
  • Chronic allograft rejection
  • Cyclosporine
  • Obliterative bronchiolitis
  • Regulatory T cells

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

CD28 down-regulation on CD4 T cells is a marker for graft dysfunction in lung transplant recipients. / Studer, Sean M.; George, M. Patricia; Zhu, Xuehai; Song, Yifang; Valentine, Vincent G.; Stoner, Michael W.; Sethi, Jigme; Steele, Chad; Duncan, Steven R.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 178, No. 7, 01.10.2008, p. 765-773.

Research output: Contribution to journalArticle

Studer, SM, George, MP, Zhu, X, Song, Y, Valentine, VG, Stoner, MW, Sethi, J, Steele, C & Duncan, SR 2008, 'CD28 down-regulation on CD4 T cells is a marker for graft dysfunction in lung transplant recipients', American Journal of Respiratory and Critical Care Medicine, vol. 178, no. 7, pp. 765-773. https://doi.org/10.1164/rccm.200701-013OC
Studer, Sean M. ; George, M. Patricia ; Zhu, Xuehai ; Song, Yifang ; Valentine, Vincent G. ; Stoner, Michael W. ; Sethi, Jigme ; Steele, Chad ; Duncan, Steven R. / CD28 down-regulation on CD4 T cells is a marker for graft dysfunction in lung transplant recipients. In: American Journal of Respiratory and Critical Care Medicine. 2008 ; Vol. 178, No. 7. pp. 765-773.
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abstract = "Rationale: Repeated antigen-driven proliferations cause CD28 on T cells to down-regulate. We hypothesized that alloantigen-induced proliferations could cause CD28 down-regulation in lung transplant recipients. Objectives: To ascertain if CD28 down-regulation on CD4 T cells associated with manifestations of allograft dysfunction in lung transplant recipients. Methods: Peripheral blood CD4 T cells from 65 recipients were analyzed by flow cytometry, cytokine multiplex and proliferative assays, and correlated with clinical events. Measurements and Main Results: Findings that CD28 was present on less than 90{\%} of total CD4 T cells were predominantly seen among the recipients with bronchiolitis obliterans syndrome (specificity = 88{\%}). Perforin and granzyme B were produced by >50{\%} of the CD4+CD28null cells, but less than 6{\%} of autologous CD4+CD28+ cells (P < 0.006). CD4+CD28null cells also had increased productions of proinflammatory cytokines, but less frequently expressed regulatory T-cell marker FoxP3 (2.1 ± 1.3{\%}), compared with autologous CD4 +CD28+ (9.5 ± 1.4; P = 0.01). Cyclosporine A (100 ng/ml) inhibited proliferation of CD4+CD28null cells by 33 ± 11{\%} versus 68 ± 12{\%} inhibition of CD4+CD28 + (P = 0.025). FEV1 fell 6 months later (0.35±0.04L) in recipients with CD4+CD28+/CD4 total less than 90{\%} (CD28{\%} Low) compared with 0.08 ± 0.08 L among CD4+CD28+/CD4total (CD28{\%} High) greater than 90{\%} (CD28{\%} High) recipients (P = 0.013). Two-year freedom from death or retransplantation in CD28{\%} Low recipients was 32 ± 10{\%} versus 78 ± 6{\%} among the CD28{\%} High subjects (P < 0.0001). Conclusions: CD28 down-regulation on CD4 cells is associated with bronchiolitis obliterans syndrome and poor outcomes in lung transplantation recipients. CD4 +CD28null cells have unusual, potentially pathogenic characteristics, and could be important in the progression of allograft dysfunction. These findings may illuminate a novel paradigm of transplantation immunopathogenesis, and suggest that CD28 measurements could identify recipients at risk for clinical deteriorations.",
keywords = "Bronchiolitis obliterans syndrome, Chronic allograft rejection, Cyclosporine, Obliterative bronchiolitis, Regulatory T cells",
author = "Studer, {Sean M.} and George, {M. Patricia} and Xuehai Zhu and Yifang Song and Valentine, {Vincent G.} and Stoner, {Michael W.} and Jigme Sethi and Chad Steele and Duncan, {Steven R.}",
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T1 - CD28 down-regulation on CD4 T cells is a marker for graft dysfunction in lung transplant recipients

AU - Studer, Sean M.

AU - George, M. Patricia

AU - Zhu, Xuehai

AU - Song, Yifang

AU - Valentine, Vincent G.

AU - Stoner, Michael W.

AU - Sethi, Jigme

AU - Steele, Chad

AU - Duncan, Steven R.

PY - 2008/10/1

Y1 - 2008/10/1

N2 - Rationale: Repeated antigen-driven proliferations cause CD28 on T cells to down-regulate. We hypothesized that alloantigen-induced proliferations could cause CD28 down-regulation in lung transplant recipients. Objectives: To ascertain if CD28 down-regulation on CD4 T cells associated with manifestations of allograft dysfunction in lung transplant recipients. Methods: Peripheral blood CD4 T cells from 65 recipients were analyzed by flow cytometry, cytokine multiplex and proliferative assays, and correlated with clinical events. Measurements and Main Results: Findings that CD28 was present on less than 90% of total CD4 T cells were predominantly seen among the recipients with bronchiolitis obliterans syndrome (specificity = 88%). Perforin and granzyme B were produced by >50% of the CD4+CD28null cells, but less than 6% of autologous CD4+CD28+ cells (P < 0.006). CD4+CD28null cells also had increased productions of proinflammatory cytokines, but less frequently expressed regulatory T-cell marker FoxP3 (2.1 ± 1.3%), compared with autologous CD4 +CD28+ (9.5 ± 1.4; P = 0.01). Cyclosporine A (100 ng/ml) inhibited proliferation of CD4+CD28null cells by 33 ± 11% versus 68 ± 12% inhibition of CD4+CD28 + (P = 0.025). FEV1 fell 6 months later (0.35±0.04L) in recipients with CD4+CD28+/CD4 total less than 90% (CD28% Low) compared with 0.08 ± 0.08 L among CD4+CD28+/CD4total (CD28% High) greater than 90% (CD28% High) recipients (P = 0.013). Two-year freedom from death or retransplantation in CD28% Low recipients was 32 ± 10% versus 78 ± 6% among the CD28% High subjects (P < 0.0001). Conclusions: CD28 down-regulation on CD4 cells is associated with bronchiolitis obliterans syndrome and poor outcomes in lung transplantation recipients. CD4 +CD28null cells have unusual, potentially pathogenic characteristics, and could be important in the progression of allograft dysfunction. These findings may illuminate a novel paradigm of transplantation immunopathogenesis, and suggest that CD28 measurements could identify recipients at risk for clinical deteriorations.

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KW - Bronchiolitis obliterans syndrome

KW - Chronic allograft rejection

KW - Cyclosporine

KW - Obliterative bronchiolitis

KW - Regulatory T cells

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