PD-1 expression and IL-2 loss of cytomegalovirus- specific T cells correlates with viremia and reversible functional anergy.
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.
Department of Internal Medicine IV, University of the Saarland, D-66421 Homburg, Germany.
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Sester
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Presser
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Dirks
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Gärtner
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Köhler
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Sester
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000096:biosynthesis*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology; D016022:Case-Control Studies; D017635:Clonal Anergy; D003587:Cytomegalovirus / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000378:metabolism* / Q000821:virology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D019562:Viral Load; D014766:Viremia / Q000378:metabolism; D014779:Virus Replication
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D007376:Interleukin-2; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor