PD-1 expression and IL-2 loss of cytomegalovirus- specific T cells correlates with viremia and reversible functional anergy

Am J Transplant. 2008 Jul;8(7):1486-97. doi: 10.1111/j.1600-6143.2008.02279.x.


Cytomegalovirus (CMV) represents a major cause of infectious complications after transplantation. Recently, chronic infections with lymphocyte choriomeningitis virus (LCMV), HIV or HCV were shown to be associated with functionally exhausted T cells characterized by high expression of the programmed death (PD)-1 molecule and altered cytokine expression patterns. We therefore hypothesized that functional exhaustion of CMV-specific CD4 T cells may determine impaired CMV control in patients after renal transplantation. In viremic transplant recipients, a significantly higher proportion of CMV-specific CD4 T cells was PD-1 positive (median 40.9%, 17.0-88.7%) as compared to nonviremic transplant patients (8.8%, 0.8-80.5%), dialysis patients (8.8%, 0-36.7%) or controls (3.2%, 0.3-15.4%, p < 0.0001). In line with functional impairment, PD-1-positive T cells produced significantly less IFNgamma as compared to PD-1-negative T cells (p < 0.0001). Moreover, unlike controls or nonviremic patients, CMV-specific T cells from viremic patients showed a significant loss of IL-2 production (p < 0.0001). Interestingly, functional anergy of CMV-specific CD4 T cells was reversible in that antibody-mediated blockade of PD-1 signaling with its ligands PD-L1/-L2 led to an up to 10-fold increase in CMV-specific proliferation. In conclusion, expression of PD-1 defines a reversible defect of CMV-specific CD4 T cells that is associated with viremia, and blocking PD-1 signaling may provide a potential target for enhancing the function of exhausted T cells in chronic CMV infection.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antigens, CD / biosynthesis*
  • Apoptosis Regulatory Proteins / biosynthesis*
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD4-Positive T-Lymphocytes / virology
  • Case-Control Studies
  • Clonal Anergy
  • Cytomegalovirus / metabolism
  • Cytomegalovirus Infections / metabolism*
  • Cytomegalovirus Infections / virology
  • Female
  • Gene Expression
  • Humans
  • Interleukin-2 / biosynthesis*
  • Kidney Transplantation*
  • Male
  • Middle Aged
  • Programmed Cell Death 1 Receptor
  • Viral Load
  • Viremia / metabolism
  • Virus Replication


  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • Interleukin-2
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor