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 Tx patients presented significant expansion of the CD56brightCD16± subset and displayed effective NK cell function, while PTLD patients accumulated CD56dimCD16− 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 didn’t 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.

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

“…In these studies the expression of PD-1 was detected in PB NK cells derived from patients 37,38,59,60 but not from HDs. In addition, the level of expression reported was very low, thus rendering it difficult to discriminate between PD-1 1 and PD-1 2 cells and to identify a distinct subset of PD-1 1 cells.…”

“…34,35 A constitutive or inducible expression of PD-1 has been detected in different cell populations, including T, B, and myeloid cells, 14,36 whereas little is known regarding PD-1 expression on NK cells to date. In human subjects it has been reported that NK cells from patients with multiple myeloma 37 or patients with posttransplantation lymphoproliferative disorders 38 can express low PD-1 levels. On the other hand, expression of PD-1 by resting NK cells from immunocompetent healthy subjects has been poorly defined.…”

Interferon-γ-induced activation of JAK1 and JAK2 suppresses tumor cell susceptibility to NK cells through upregulation of PD-L1 expression

“…C NK cells in all donors 28,29 and was increased after IL-2 activation while IFNg had no effect on NK cell PD-1 expression (Fig. S5).…”

Metabolic regulation of immune responses: therapeutic opportunities

“…NK cell phenotypes (78)(79)(80)(81)(82)(83)(84). Therefore, many of the same conditions can exist at sites of viral and bacterial infection as seen in the tumor microenvironment.…”