Author(s): Sester U, Presser D, Dirks J, Grtner BC, Khler H,
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Abstract 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.
This article was published in Am J Transplant
and referenced in Journal of Clinical & Cellular Immunology