title: Cytomegalovirus-Associated CD4(+) CD28(null) Cells in NKG2D-Dependent Glomerular Endothelial Injury and Kidney Allograft Dysfunction.
abstract: Emerging data suggest that expansion of a circulating population of atypical, cytotoxic CD4(+) T cells lacking costimulatory CD28 (CD4(+) CD28(null) cells) is associated with latent cytomegalovirus (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. Multicolor flow cytometry of peripheral blood mononuclear cells before transplantation and serially posttransplantation was undertaken. CD4(+) CD28(null) cells were found predominantly in CMV-seropositive patients and expanded in the posttransplantation 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 peripheral blood mononuclear cells 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 estimated glomerular filtration rate 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.
authors.affiliation: Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital Birmingham, Birmingham, UK.|Centre for Translational Inflammation Research, University of Birmingham, Birmingham, UK.
authors.forename: S
authors.initials: S
authors.lastname: Shabir
authors.affiliation: Centre for Translational Inflammation Research, University of Birmingham, Birmingham, UK.
authors.forename: H
authors.initials: H
authors.lastname: Smith
authors.affiliation: Centre for Translational Inflammation Research, University of Birmingham, Birmingham, UK.|School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: B
authors.initials: B
authors.lastname: Kaul
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: A
authors.initials: A
authors.lastname: Pachnio
authors.affiliation: Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital Birmingham, Birmingham, UK.|Centre for Translational Inflammation Research, University of Birmingham, Birmingham, UK.
authors.forename: S
authors.initials: S
authors.lastname: Jham
authors.affiliation: Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: S
authors.initials: S
authors.lastname: Kuravi
authors.affiliation: Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital Birmingham, Birmingham, UK.|Centre for Translational Inflammation Research, University of Birmingham, Birmingham, UK.
authors.forename: S
authors.initials: S
authors.lastname: Ball
authors.affiliation: Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital Birmingham, Birmingham, UK.|Centre for Translational Inflammation Research, University of Birmingham, Birmingham, UK.
authors.forename: S
authors.initials: S
authors.lastname: Chand
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: P
authors.initials: P
authors.lastname: Moss
authors.affiliation: Centre for Translational Inflammation Research, University of Birmingham, Birmingham, UK.
authors.forename: L
authors.initials: L
authors.lastname: Harper
authors.affiliation: Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital Birmingham, Birmingham, UK.|Centre for Translational Inflammation Research, University of Birmingham, Birmingham, UK.
authors.forename: R
authors.initials: R
authors.lastname: Borrows
mesh_terms: D064591:Allografts; D018106:CD28 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000150:complications / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D051799:Delayed Graft Function / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000276:immunology* / Q000293:injuries / Q000821:virology; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006085:Graft Survival; D006801:Humans; D007676:Kidney Failure, Chronic / Q000601:surgery; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000276:immunology* / Q000293:injuries / Q000821:virology; D016030:Kidney Transplantation / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D018106:CD28 Antigens; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K