title: Decreased NKp46 and NKG2D and elevated PD-1 are associated with altered NK-cell function in pediatric transplant patients with PTLD.
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 CD56(bright) CD16(±)  subset and displayed effective NK-cell function, while PTLD patients accumulated CD56(dim) CD16(-)  and CD56(-) CD16(+)  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.
authors: Thomas E. Starzl Transplantation Institute, Pittsburgh, PA 15213, USA.
authors: Silke
authors: S
authors: Wiesmayr
authors: Steven A
authors: SA
authors: Webber
authors: Camila
authors: C
authors: Macedo
authors: Iulia
authors: I
authors: Popescu
authors: Louise
authors: L
authors: Smith
authors: Jane
authors: J
authors: Luce
authors: Diana
authors: D
authors: Metes
mesh_terms: D000293:Adolescent; D019002:CD56 Antigen / Q000378:metabolism; D048708:Cell Growth Processes; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003602:Cytotoxicity, Immunologic; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D016027:Heart Transplantation; D004854:Herpesvirus 4, Human / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D007165:Immunosuppression Therapy; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D016040:Lung Transplantation; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000276:immunology*; D008297:Male; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011183:Postoperative Complications; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D019002:CD56 Antigen; C527085:KLRK1 protein, human; C112260:NCR1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor