title: Retuning of Mouse NK Cells after Interference with MHC Class I Sensing Adjusts Self-Tolerance but Preserves Anticancer Response.
abstract: Natural killer (NK) cells are most efficient if their targets do not express self MHC class I, because NK cells carry inhibitory receptors that interfere with activating their cytotoxic pathway. Clinicians have taken advantage of this by adoptively transferring haploidentical NK cells into patients to mediate an effective graft-versus-leukemia response. With a similar rationale, antibody blockade of MHC class I-specific inhibitory NK cell receptors is currently being tested in clinical trials. Both approaches are challenged by the emerging concept that NK cells may constantly adapt or "tune" their responsiveness according to the amount of self MHC class I that they sense on surrounding cells. Hence, these therapeutic attempts would initially result in increased killing of tumor cells, but a parallel adaptation process might ultimately lead to impaired antitumor efficacy. We have investigated this question in two mouse models: inhibitory receptor blockade in vivo and adoptive transfer to MHC class I-disparate hosts. We show that changed self-perception via inhibitory receptors in mature NK cells reprograms the reactivity such that tolerance to healthy cells is always preserved. However, reactivity against cancer cells lacking critical MHC class I molecules (missing self-reactivity) still remains or may even be increased. This dissociation between activity against healthy cells and tumor cells may provide an answer as to why NK cells mediate graft-versus-leukemia effects without causing graft-versus-host disease and may also be utilized to improve immunotherapy.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Arnika Kathleen
authors.initials: AK
authors.lastname: Wagner
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Stina Linnea
authors.initials: SL
authors.lastname: Wickström
authors.affiliation: Department of Experimental and Clinical Medicine, University of "Magna Graecia," Catanzaro, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Tallerico
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sadia
authors.initials: S
authors.lastname: Salam
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Tadepally
authors.initials: T
authors.lastname: Lakshmikanth
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Brauner
authors.affiliation: Center for Hematology and Regenerative Medicine (HERM), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Petter
authors.initials: P
authors.lastname: Höglund
authors.affiliation: Department of Experimental and Clinical Medicine, University of "Magna Graecia," Catanzaro, Italy.
authors.forename: Ennio
authors.initials: E
authors.lastname: Carbone
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maria Helena
authors.initials: MH
authors.lastname: Johansson
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. klas.karre@ki.se.
authors.forename: Klas
authors.initials: K
authors.lastname: Kärre
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism*; D007108:Immune Tolerance; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D037181:Lectins, C-Type; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D015395:Histocompatibility Antigens Class I; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D011971:Receptors, Immunologic