PD‐1 Analysis on CD28−CD27− CD4 T Cells Allows Stimulation‐Independent Assessment of CMV Viremic Episodes in Transplant Recipients

• Published in: American journal of transplantation Vol. 13; no. 12; pp. 3132 - 3141
• Main Authors: Dirks, J., Tas, H., Schmidt, T., Kirsch, S., Gärtner, B. C., Sester, U., Sester, M.
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley 01-12-2013; Elsevier Limited
• Subjects: Adult; Antiviral Agents - chemistry; Biological and medical sciences; Case-Control Studies; CD27; CD28; CD28 Antigens - metabolism; CD4-Positive T-Lymphocytes - cytology; Cross-Sectional Studies; Cytomegalovirus; Cytomegalovirus Infections - complications; Flow Cytometry; Humans; Infections; Infectious diseases; Kidney Transplantation; Lymphocytes; Medical sciences; Middle Aged; monitoring; Phenotype; Postoperative Complications; Programmed Cell Death 1 Receptor - metabolism; Renal Dialysis; Renal Insufficiency - blood; Renal Insufficiency - complications; Renal Insufficiency - therapy; Sensitivity and Specificity; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; T cell; transplantation; Transplants & implants; Tumor Necrosis Factor Receptor Superfamily, Member 7 - metabolism; Viral diseases; Viremia - complications; Opportunistic infection; CD4 T lymphocyte; Herpesviridae; T cell; Stimulation; Transplantation; Programmed cell death protein 1; Homotransplantation; Betaherpesvirinae; Costimulatory molecule; Human cytomegalovirus; Infection; Virus; Treatment; Surveillance; cytomegalovirus; Surgery; Analysis; Viral disease; T-Lymphocyte; CD28; Graft; CD27; Monitoring; monitoring; transplantation
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/ajt.12480

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.
This study demonstrates that the presence of CD28‐ CD27‐ CD4 T cells is associated with a positive CMV infection status and that increased PD‐1 expression on CD28‐ CD27‐ CD4 T cells correlates with CMV viremia in transplant recipients.