Expansion of cytolytic CD4+CD28− T cells in end-stage renal disease

Betjes, Michiel G. H.; Huisman, Martin; Weimar, Willem; Litjens, Nicolle H.R.

doi:10.1038/ki.2008.301

Cited by 102 publications

(134 citation statements)

References 26 publications

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“…CMV prophylaxis with 100 days of valganciclovir was given to the D+RÀ serostatus group only, with dose adjustment for renal function. Serial whole blood samples were taken for CMV DNA polymerase chain reaction in all patients at day 0 (before transplantation) and then at weeks 1,2,3,4,6,8,10,12,16,20,24,28,34,40,46, and 52. The clinical team remained unaware of these results, and no changes in clinical management ensued (it is not unit policy to undertake viral load testing and preemptive therapy in the context of asymptomatic CMV infection, as is the case in most centers, so these assessments were undertaken for research purposes only).…”

Section: Assessment Of CMV Serostatus Infection and Diseasementioning

confidence: 99%

“…In contrast to CD28-expressing CD4 + cells (CD4 + CD28 + ), CD4 + CD28 null cells express cytotoxic mediators such as perforin (4,5,8), and cells isolated from patients with acute coronary syndromes promote damage to human umbilical vein endothelial cells in vitro (9). Interestingly, exposure of CD4 + cells to CMV antigens (but not other viral antigens) promotes expansion of CD4 + cells expressing the killer lectin-like receptor NKG2D (10,11), also uncommonly expressed on CD4 + T cells (10).…”

Section: Introductionmentioning

confidence: 99%

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Cytomegalovirus-Associated CD4+CD28null Cells in NKG2D-Dependent Glomerular Endothelial Injury and Kidney Allograft Dysfunction

Shabir

Smith

Kaul

et al. 2016

American Journal of Transplantation

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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 CD4null 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 + CD28null 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.

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Section: Assessment Of CMV Serostatus Infection and Diseasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cytomegalovirus-Associated CD4+CD28null Cells in NKG2D-Dependent Glomerular Endothelial Injury and Kidney Allograft Dysfunction

Shabir

Smith

Kaul

et al. 2016

American Journal of Transplantation

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“…A characteristic feature of these differentiated T cells in CMV-seropositive individuals is the higher number of CD4 þ as well as CD8 þ T cells lacking the surface expression of CD28, a costimulatory molecule that is lost late in the course of T cell differentiation (5,6). In particular, the appearance of significant numbers of circulating CD4 þ CD28null T cells is related to CMV seropositivity and ESRD further promotes their expansion (7,8). CMV infection also contributes to the uremia-associated premature immunological aging of ESRD patients as it is associated with a reduced telomere length in CD8 þ T cells (3).…”

Section: Introductionmentioning

confidence: 99%

Primary Cytomegalovirus Infection Significantly Impacts Circulating T Cells in Kidney Transplant Recipients

Meijers

Litjens

Hesselink

et al. 2015

American Journal of Transplantation

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Cytomegalovirus (CMV) infection profoundly affects the T cell compartment and is associated with alterations in T cell aging parameters and generation of cytotoxic CD4þ CD28null T cells. Hence, the effect of a primary CMV infection post-kidney transplantation (KT) on the peripheral T cell compartment was examined. As aging parameters, we determined the T cell differentiation status, T cell receptor excision circle (TREC) content, CD31þ na€ ıve T cell numbers and relative telomere length (RTL) pre-KT and 12 months post-KT. CMV-seronegative KT recipients, receiving a kidney from a CMV-seropositive donor (Dþ/RÀ) were compared to Dþ/Rþ KT recipients. Eleven out of the 22 Dþ/RÀ KT recipients had CMV viremia post-KT. They developed CMV-specific CD4 þ and CD8 þ T cells and their T cell compartment shifted towards a more differentiated memory phenotype with expansion of CD4 þ CD28null and CD8 þ CD28null cells. One year post-KT, the CD8 þ T cell count was almost doubled compared to nonviremic Dþ/RÀ and Dþ/Rþ KT recipients. In addition, the RTL of the CD8 þ T cell was significantly lower and both the TREC content and CD31 þ na€ ıve T cell numbers significantly decreased. Moreover, primary CMV infection was associated with a negative impact on glomerular filtration rate. In conclusion, primary CMV infection has a substantial impact on the number and phenotype of peripheral T cells and may negatively affect renal allograft function.

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“…21,[25][26][27] Our study provides the first direct evidence for the presence of hCMV protein in renal biopsy specimens from CKD kidneys. Furthermore, it is the first to demonstrate an inverse correlation between the level of hCMV IgG and hematocrit in a CKD cohort.…”

Section: Discussionmentioning

confidence: 68%

Human Cytomegalovirus Inhibits Erythropoietin Production

Butler

Džabić

Bakker

et al. 2014

Journal of the American Society of Nephrology

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Anemia is a feature of CKD and a complication of renal transplantation, often caused by impaired production of erythropoietin. The kidney is a target organ for human cytomegalovirus (hCMV) in such patients, but it is not known whether hCMV effects erythropoietin production. We found that kidneys from patients with CKD were positive for hCMV protein and that blood levels of hCMV IgG inversely correlated with red blood cell count. In mice, systemic murine cytomegalovirus infection decreased serum erythropoietin levels. In human erythropoietin-producing cells, hCMV inhibited hypoxia-induced expression of erythropoietin mRNA and protein. hCMV early gene expression was responsible, as ultravioletinactivated virus had no effect and valganciclovir treatment showed that late gene expression was nonessential. Hypoxia-induced gene transcription is controlled by the transcription factors hypoxiainducible transcription factor (HIF)-1a and HIF2a, which are constitutively produced but stable only under low oxygen conditions. We found that hCMV inhibited constitutive production of HIF2a mRNA. HIF2a is thought to be the master regulator of erythropoietin transcription. Single-cell analysis revealed that nuclear accumulation of HIF2a was inhibited in hCMV-infected cells, and the extent of inhibition correlated with hCMV protein expression. Our findings suggest that renal hCMV infection could induce or exacerbate anemia in patients. 25: 166925: -167825: , 201425: . doi: 10.1681 Anemia is a frequent feature of CKD and a common complication of renal transplantation. Large cohort studies have shown that around 40% of patients develop anemia following transplant surgery. 1-4 Interestingly, the incidence of anemia is unexpectedly high in patients with an otherwise functioning renal transplant (for review, see Vanrenterghem 5 ). Most evidence to date suggests that impaired erythropoietin (EPO) production by the renal allograft is the most common cause of post-transplant anemia. 5 In patients with CKD, as renal function decreases the incidence of anemia increases, to .70% in patients with CKD stage 5. Although its cause is multifactorial, a significant factor is inadequate production of EPO. The mechanisms behind the impaired renal EPO production remain to be elucidated. 6 EPO is a glycoprotein hormone, produced primarily in the kidney, that controls erythropoiesis and regulates hematocrit. 7 Treatment with recombinant EPO can correct post-transplant and renal diseaseassociated anemia, 8 although the cause of EPO loss is unknown. In adults, EPO originates mainly from fibroblast-type cells in the renal cortex 9 and is controlled by heterodimeric (a/b) hypoxia-inducible transcription (HIF) factors. Under normoxic conditions, HIFa subunits (HIF1a and HIF2a) are constitutively produced but are subject to rapid proteasomal degradation by the von Hippel-Lindau tumor suppressor, the recognition complex of an E3 ubiquitin J Am Soc Nephrol

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Expansion of cytolytic CD4+CD28− T cells in end-stage renal disease

Cited by 102 publications

References 26 publications

Cytomegalovirus-Associated CD4+CD28null Cells in NKG2D-Dependent Glomerular Endothelial Injury and Kidney Allograft Dysfunction

Cytomegalovirus-Associated CD4+CD28null Cells in NKG2D-Dependent Glomerular Endothelial Injury and Kidney Allograft Dysfunction

Primary Cytomegalovirus Infection Significantly Impacts Circulating T Cells in Kidney Transplant Recipients

Human Cytomegalovirus Inhibits Erythropoietin Production

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