Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44.
NK cells play an important role in the early immune response to cancer. The NKp44 activating receptor is the only natural cytotoxicity receptor that is expressed exclusively by primate NK cells, yet its cellular ligands remain largely unknown. Proliferating cell nuclear Ag (PCNA) is overexpressed in cancer cells. In this study, we show that the NKp44 receptor recognizes PCNA. Their interaction inhibits NK cell function through NKp44/ITIM. The physical interaction of NKp44 and PCNA is enabled by recruitment of target cell PCNA to the NK immunological synapse. We demonstrate that PCNA promotes cancer survival by immune evasion through inhibition of NKp44-mediated NK cell attack.
Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
Benyamin
B
Rosental
Michael
M
Brusilovsky
Uzi
U
Hadad
Dafna
D
Oz
Michael Y
MY
Appel
Fabian
F
Afergan
Rami
R
Yossef
Lior Ann
LA
Rosenberg
Amir
A
Aharoni
Adelheid
A
Cerwenka
Kerry S
KS
Campbell
Alex
A
Braiman
Angel
A
Porgador
D015153:Blotting, Western; D045744:Cell Line, Tumor; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology; D047468:Immunoprecipitation; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D018613:Microscopy, Confocal; D055629:Natural Cytotoxicity Triggering Receptor 2 / Q000276:immunology*; D018809:Proliferating Cell Nuclear Antigen / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D019139:Tumor Escape / Q000276:immunology*
D008024:Ligands; C112837:NCR2 protein, human; D055629:Natural Cytotoxicity Triggering Receptor 2; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering