Decreased NKp46 and NKG2D and elevated PD-1 are associated with altered NK-cell function in pediatric transplant patients with PTLD

Authors

  • Silke Wiesmayr,

    1. Thomas E. Starzl Transplantation Institute, Pittsburgh, PA, USA
    2. Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
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  • Steven A. Webber,

    1. Thomas E. Starzl Transplantation Institute, Pittsburgh, PA, USA
    2. Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA, USA
    3. Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA
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  • Camila Macedo,

    1. Thomas E. Starzl Transplantation Institute, Pittsburgh, PA, USA
    2. Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
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  • Iulia Popescu,

    1. Thomas E. Starzl Transplantation Institute, Pittsburgh, PA, USA
    2. Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
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  • Louise Smith,

    1. Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA, USA
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  • Jane Luce,

    1. Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA, USA
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  • Diana Metes

    Corresponding author
    1. Thomas E. Starzl Transplantation Institute, Pittsburgh, PA, USA
    2. Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
    3. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
    • Thomas E. Starzl Transplantation Institute (E 1549), 200 Lothrop Street, Pittsburgh, PA 15213, USA Fax: +1-412-624-6666===

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Abstract

Post-transplantation lymphoproliferative disorders (PTLD) are life-threatening complications of organ transplantation caused by EBV infection and the use of chronic immunosuppression. While T-cell impairment is known to play a critical role in the immunopathogenesis of EBV complications post-transplantation, the role of NK cells is still under investigation. Here, we have characterized NK-cell phenotype and function in peripheral blood from asymptomatic pediatric thoracic transplant patients, patients with PTLD, and healthy controls. Overall, asymptomatic pediatric solid organ transplant (Tx) patients presented significant expansion of the CD56brightCD16± subset and displayed effective NK-cell function, while PTLD patients accumulated CD56dimCD16 and CD56CD16+ NK-cell subsets. In addition, NK cells from PTLD patients down-regulated NKp46 and NKG2D, and significantly up-regulated PD-1. These phenotypic changes were associated with NK functional impairment, resembling cellular exhaustion. Disrupting PD-1 inhibitory pathway improved IFN-γ release, but did not enhance cytotoxicity in PTLD patients, suggesting that these defects were partially PD-1 independent. Our results indicate the important role of NK cells during EBV surveillance post-transplantation, with implications for the immunopathogenesis of EBV complications, and suggest that monitoring NK cells in transplant patients may hold clinical value.

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