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PD‐1 Expression and IL‐2 Loss of Cytomegalovirus‐ Specific T Cells Correlates with Viremia and Reversible Functional Anergy
Author(s) -
Sester U.,
Presser D.,
Dirks J.,
Gärtner B. C.,
Köhler H.,
Sester M.
Publication year - 2008
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2008.02279.x
Subject(s) - viremia , medicine , immunology , transplantation , cytomegalovirus , cytokine , virus , viral disease , herpesviridae
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 IFNγ 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.