Activating natural killer cell receptors: KIR recognition of a cancer-associated ligand

Abstract

Natural killer (NK) cells recognize and kill cancer cells and infected cells. How NK cells discriminate between cancer cells and normal cells is not fully known. In this thesis we have found that an activating receptor (KIR2DS2) in the immunoglobulin receptor (KIR) family binds a protein ligand on carcinoma cell lines. The data indicate that the cancer ligand is also recognized by a similar inhibitory receptor (KIR2DL3). The only presently known ligand for these receptors is HLA-C. We show that the cancer ligand, unlike HLA-C, does not depend on β2-microglobulin. The cancer cells shed the ligand into the surrounding fluid and the ligand can be purified by size and charge while maintaining reactivity with KIR2DS2. Initial mass spectrometry experiments have not identified the cancer ligand. We also investigated the adaptor proteins DAP10 and DAP12 that associate to activating NK receptors, and initiate two different intracellular signaling pathways that activate NK cells. Biochemical analysis in transfected cells indicated that the adaptors can form heterodimers (DAP10/DAP12) and that both can bind to activating receptors in human, rat and mouse more promiscuously than previously shown.