title: Chemotherapy-induced genotoxic stress promotes sensitivity to natural killer cell cytotoxicity by enabling missing-self recognition.
abstract: Natural killer (NK) cells can recognize and kill tumor cells lacking "self" markers, such as class I MHC, but the basis for this recognition is not completely understood. NKR-P1 receptors are members of the C-type lectin-related NK receptor superfamily that are conserved from rodents to humans. Identification of Clr ligands for the NKR-P1 receptors has facilitated functional analysis of MHC-independent target cell recognition by NK cells. One receptor-ligand pair, NKR-P1B:Clr-b, can mediate "missing-self" recognition of tumor and infected cells, but the role of this axis in sensing stressed cells remains unknown. Here, we show that Clr-b is rapidly downregulated in cells undergoing genotoxic and cellular stress at the level of both RNA and surface protein. Stress-mediated loss of Clr-b on leukemia cells enhanced cytotoxicity mediated by NKR-P1B(+) NK cells. Notably, Clr-b downregulation was coordinated functionally with stress-mediated upregulation of NKG2D ligands (but not class I MHC). Our findings highlight a unique role for the MHC-independent NKR-P1B:Clr-b missing-self axis in recognition of stressed cells, and provide evidence of two independent levels of Clr-b regulation in stressed cells.
authors.affiliation: Department of Immunology, University of Toronto, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Fine
authors.forename: Peter
authors.initials: P
authors.lastname: Chen
authors.forename: Aruz
authors.initials: A
authors.lastname: Mesci
authors.forename: David S J
authors.initials: DS
authors.lastname: Allan
authors.forename: Stephan
authors.initials: S
authors.lastname: Gasser
authors.forename: David H
authors.initials: DH
authors.lastname: Raulet
authors.forename: James R
authors.initials: JR
authors.lastname: Carlyle
mesh_terms: D000818:Animals; D016590:Aphidicolin / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D001761:Bleomycin / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D041681:NIH 3T3 Cells; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000276:immunology; D000077546:Roscovitine; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D037181:Lectins, C-Type; D008565:Membrane Proteins; C429003:Ocil protein, mouse; D011687:Purines; D011971:Receptors, Immunologic; D025521:Tumor Suppressor Proteins; D000077546:Roscovitine; D001761:Bleomycin; D016590:Aphidicolin; C576897:Atr protein, mouse; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D002945:Cisplatin
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