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CD28 Down-Regulation on CD4 T Cells Is a Marker for Graft Dysfunction in Lung Transplant Recipients

¹ Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; ² Department of Medicine, University of Texas, Medical Branch Galveston, Galveston, Texas; and ³ Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Steven R. Duncan, M.D., Pulmonary, Allergy, and Critical Care Medicine, 628 NW MUH, 3459 Fifth Avenue, University of Pittsburgh, Pittsburgh, PA 15213. E-mail: duncsr{at}upmc.edu

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⁺CD28^null cells, but less than 6% of autologous CD4⁺CD28⁺ cells (P < 0.006). CD4⁺CD28^null 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⁺CD28^null cells by 33 ± 11% versus 68 ± 12% inhibition of CD4⁺CD28⁺ (P = 0.025). FEV₁ fell 6 months later (0.35 ± 0.04 L) in recipients with CD4⁺CD28⁺/CD4_total less than 90% (CD28% Low) compared with 0.08 ± 0.08 L among CD4⁺CD28⁺/CD4_total (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⁺CD28^null 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.

Key Words: bronchiolitis obliterans syndrome • obliterative bronchiolitis • chronic allograft rejection • regulatory T cells • cyclosporine

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject It is known that some lung transplant recipients develop severe, progressive chronic allograft rejection, but many of the pathogenetic details remain unknown. What This Study Adds to the Field 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.