Sammendrag
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.
Artikkelliste
Article I: Lavanya Thiruchelvam-Kyle, Sigurd E. Hoelsbrekken, Per C. Saether, Elisabeth G. Bjørnsen, Daniela Pende, Sigbjørn Fossum, Michael R. Daws and Erik Dissen. 2017. The activating human NK cell receptor KIR2DS2 recognizes a β2-microglobulin independent ligand on cancer cells. Journal of Immunology 198:2556-2567. The paper is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.4049/jimmunol.1600930 |
Article II: Lavanya Thiruchelvam-Kyle, Maria Stensland, Elisabeth G. Bjørnsen, Per Christian Saether, Bernd Thiede, Michael R. Daws, Tuula A. Nyman, and Erik Dissen. A soluble ligand for the activating NK cell receptor KIR2DS2 is produced by cancer cells. Manuscript. To be published. The paper is not available in DUO awaiting publishing. |
Article III: Per Christian Saether, Lavanya Thiruchelvam-Kyle, Sigurd E. Hoelsbrekken, Michael R. Daws and Erik Dissen. Co-operative interaction of the activating transmembrane adaptor proteins DAP10 and DAP12 with NK cell receptors. Manuscript. To be published. The paper is not available in DUO awaiting publishing. |