title: PD-1 analysis on CD28(-) CD27(-) CD4 T cells allows stimulation-independent assessment of CMV viremic episodes in transplant recipients.
abstract: Expression of the inhibitory receptor programmed death 1 (PD-1) on cytomegalovirus (CMV)-specific CD4 T cells defines a phenotype associated with CMV viremia in transplant recipients. Moreover, CD28(-) CD27(-) double negativity is known as a typical phenotype of CMV-specific CD4 T cells. Therefore, the co-expression of inhibitory receptors on CD28(-) CD27(-) CD4 T cells was assessed as a rapid, stimulation-independent parameter for monitoring CMV complications after transplantation. Ninety-three controls, 67 hemodialysis patients and 81 renal transplant recipients were recruited in a cross-sectional and longitudinal manner. CMV-specific CD4 T cell levels quantified after stimulation were compared to levels of CD28(-) CD27(-) CD4 T cells. PD-1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) expression on CD28(-) CD27(-) CD4 T cells were related to viremia. A percentage of ≥0.44% CD28(-) CD27(-) CD4 T cells defined CMV seropositivity (93.3% sensitivity, 97.1% specificity), and their frequencies correlated strongly with CMV-specific CD4 T cell levels after stimulation (r = 0.73, p < 0.0001). Highest PD-1 expression levels on CD28(-) CD27(-) CD4 T cells were observed in patients with primary CMV viremia and reactivation (p < 0.0001), whereas CTLA-4 expression was only elevated during primary CMV viremia (p < 0.05). Longitudinal analysis showed a significant increase in PD-1 expression in relation to viremia (p < 0.001), whereas changes in nonviremic patients were nonsignificant. In conclusion, increased PD-1 expression on CD28(-) CD27(-) CD4 T cells correlates with CMV viremia in transplant recipients and may serve as a specific, stimulation-independent parameter to guide duration of antiviral therapy.
authors.affiliation: Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Dirks
authors.forename: H
authors.initials: H
authors.lastname: Tas
authors.forename: T
authors.initials: T
authors.lastname: Schmidt
authors.forename: S
authors.initials: S
authors.lastname: Kirsch
authors.forename: B C
authors.initials: BC
authors.lastname: Gärtner
authors.forename: U
authors.initials: U
authors.lastname: Sester
authors.forename: M
authors.initials: M
authors.lastname: Sester
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000737:chemistry; D018106:CD28 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections / Q000150:complications*; D005434:Flow Cytometry; D006801:Humans; D016030:Kidney Transplantation; D008875:Middle Aged; D010641:Phenotype; D011183:Postoperative Complications; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D006435:Renal Dialysis; D051437:Renal Insufficiency / Q000097:blood* / Q000150:complications / Q000628:therapy; D012680:Sensitivity and Specificity; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism*; D014766:Viremia / Q000150:complications*
chemical_list: D000998:Antiviral Agents; D018106:CD28 Antigens; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7
keywords: CD27; CD28; T cell; cytomegalovirus; monitoring; transplantation