Natural Killer Cell-Mediated Shedding of ULBP2

Ruipeng Wang,Peter D Sun,Eric Vivier

doi:10.1371/journal.pone.0091133

Ruipeng Wang, Peter D Sun + Show 1 more

Open Access

https://doi.org/10.1371/journal.pone.0091133

Copy DOI

Abstract

UL16 binding proteins (ULBPs) are a family of cell surface proteins that are present in transformed and stressed cells and ligands for NKG2D. Soluble NKG2D ligands have been found in sera from cancer patients with their protein concentrations correlated with poor cancer prognosis. Here we show, for the first time, that human tumor cells lost their surface expression of ULBP2, but not ULBP1 and ULBP3, during NK cell-mediated cytolysis. In contrast to spontaneous shedding of NKG2D ligands, NK cytolysis-mediated shedding of ULBP2 was linked to target cell apoptosis, although both resulted from metalloproteinase cleavages. Inhibition of ULBP2 shedding by a metalloproteinase inhibitor BB-94 lead to reduced NK cell-mediated cytotoxicity and cytokine production. These results illustrate a regulation of NK cell effector functions through cytolysis-induced NKG2D ligand shedding. Consequently, compounds inhibiting NKG2D ligand shedding may offer therapeutic means to reduce excessive pathogenic NK cell activities.

Highlights

UL16 binding proteins (ULBPs) are a family of cell membrane proteins expressed on both transformed and stressed cells
The presence of natural killer (NK) cells significantly reduced the expression of ULBP2, but not ULBP1 or ULBP3, on Jurkat and H9 cells (Fig. 1A and B)
The percentage of ULBP2 low-target cells was closely correlated with effector-to-target ratios (E:T ratios) (Fig. S1), indicating that the loss of cell surface ULBP2 is associated with NK cell-mediated cytolysis of target cells

Summary

Introduction

UL16 binding proteins (ULBPs) are a family of cell membrane proteins expressed on both transformed and stressed cells. They were identified by their ability to bind to human cytomegalovirus protein UL16 [1]. ULBPs, as well as MHC class I-related chain (MIC) A and B proteins, are ligands of NKG2D [4,5,6], an activating receptor expressed on natural killer (NK) cells, CD8 T cells, cd T cells and some CD4 T cells [7]. Ectopic expression of mouse NKG2D ligands on tumor cells promotes NK cell recognition and enhances tumor rejection in syngeneic mice [8]. NKG2D deficiency gives rise to a higher incidence of malignancies in mice [9]

Methods

Results

Conclusion