Recognition and Killing of Human and Murine Pancreatic β Cells by the NK Receptor NKp46

Type 1 diabetes is an incurable disease that is currently treated by insulin injections or in rare cases by islet transplantation. We have recently shown that NKp46, a major killer receptor expressed by NK cells, recognizes an unknown ligand expressed by beta cells and that in the absence of NKp46, or when its activity is blocked, diabetes development is inhibited. In this study, we investigate whether NKp46 is involved in the killing of human beta cells that are intended to be used for transplantation, and we also thoroughly characterize the interaction between NKp46 and its human and mouse beta cell ligands. We show that human beta cells express an unknown ligand for NKp46 and are killed in an NKp46-dependent manner. We further demonstrate that the expression of the NKp46 ligand is detected on human beta cells already at the embryonic stage and that it appears on murine beta cells only following birth. Because the NKp46 ligand is detected on healthy beta cells, we wondered why type 1 diabetes does not develop in all individuals and show that NK cells are absent from the vicinity of islets of healthy mice and are detected in situ in proximity with beta cells in NOD mice. We also investigate the molecular mechanisms controlling NKp46 interactions with its beta cell ligand and demonstrate that the recognition is confined to the membrane proximal domain and stalk region of NKp46 and that two glycosylated residues of NKp46, Thr(125) and Asn(216), are critical for this recognition. The Journal of Immunology, 2011, 187: 3096-3103.