CMV-associated CD4(+) CD28(null) cells in NKG2D-dependent glomerular endothelial injury and kidney allograft dysfunction

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  • S Shabir
  • B Kaul
  • S Jham
  • S Ball
  • S Chand
  • L Harper
  • R Borrows


Emerging data suggests that expansion of a circulating population of atypical, cytotoxic CD4(+) T-cells lacking costimulatory CD28 ("CD4(+) CD28(null) " cells) is associated with latent CMV infection. The purpose of the current study was to increase the understanding of the relevance of these cells in 100 unselected kidney transplant recipients followed prospectively for a median of 54 months. Multicolour flow cytometry of PBMCs prior to transplantation and serially post-transplantation was undertaken. CD4(+) CD28(null) cells were found predominantly in CMV-seropositive patients, and expanded in the post-transplant period. These cells were predominantly effector-memory phenotype, and expressed markers of endothelial homing (CX3CR1) and cytotoxicity (NKG2D and perforin). Isolated CD4(+) CD27(-) CD28(null) cells proliferated in response to PBMCs previously exposed to CMV-derived (but not HLA-derived) antigens, and following such priming incubation with glomerular endothelium resulted in signs of endothelial damage and apoptosis (release of fractalkine and von Willebrand factor; increased caspase 3 expression). This effect was mitigated by NKG2D-blocking antibody. Increased CD4(+) CD28(null) cell frequencies were associated with delayed graft function, and lower eGFR at end follow-up. This study suggests an important role for this atypical cytotoxic CD4(+) CD28(null) cell subset in kidney transplantation, and points to strategies that may minimize the impact on clinical outcomes. This article is protected by copyright. All rights reserved.


Original languageEnglish
JournalAmerican Journal of Transplantation
Early online date25 Nov 2015
Publication statusE-pub ahead of print - 25 Nov 2015