# NK-cell cytotoxicity toward pluripotent stem cells and their neural progeny: impacts of activating and inhibitory receptors and KIR/HLA mismatch

## TL;DR

This study shows that pluripotent stem cells and their neural derivatives are vulnerable to NK-cell attack due to a lack of inhibitory signals and the presence of activating signals.

## Contribution

The study identifies specific activating and inhibitory receptor-ligand interactions that determine NK-cell cytotoxicity toward pluripotent stem cells and their neural progeny.

## Key findings

- Pluripotent stem cells express ligands for NKG2D, which activates NK cells, but lack sufficient inhibitory ligands like HLA-C and HLA-E.
- Neural progenitor cells and motoneurons derived from iPS cells also express B7H6, a ligand for NKp30, further promoting NK-cell activation.
- Cytotoxicity by NK cells against pluripotent stem cells and their derivatives is not significantly affected by KIR/HLA matching.

## Abstract

Pluripotent stem cells provide opportunities for treating injuries and previously incurable diseases. A major concern is the immunogenicity of stem cells and their progeny. Here, we have dissected the molecular mechanisms that allow natural killer (NK) cells to respond to human pluripotent stem cells, investigating a wide selection of activating and inhibitory NK-cell receptors and their ligands. Reporter cells expressing the activating receptor NKG2D responded strongly to embryonic stem (ES) cell lines and induced pluripotent stem (iPS) cell lines, whereas reporter cells expressing the activating receptors NKp30, NKp46, KIR2DS1, KIR2DS2, and KIR2DS4 did not respond. Human ES and iPS cells invariably expressed several ligands for NKG2D. Expression of HLA-C and HLA-E was lacking or low, insufficient to trigger reporter cells expressing the inhibitory receptors KIR2DL1, -2DL2, or -2DL3. Similar results were obtained for the pluripotent embryonic carcinoma cell lines NTERA-2 and 2102Ep, and also iPS-cell-derived neural progenitor cells. Importantly, neural progenitor cells and iPS-cell-derived motoneurons also expressed B7H6, the ligand for the activating receptor NKp30. In line with these observations, IL-2-stimulated NK cells showed robust cytotoxic responses to ES and iPS cells as well as to iPS-cell-derived motoneurons. No significant differences in cytotoxicity levels were observed between KIR/HLA matched and mismatched combinations of NK cells and pluripotent targets. Together, these data indicate that pluripotent stem cells and their neural progeny are targets for NK-cell killing both by failing to sufficiently express ligands for inhibitory receptors and by expression of ligands for activating receptors.

Graphical Abstract