title: Functional NK cell repertoires are maintained through IL-2Rα and Fas ligand.
abstract: Acquisition of a functional NK cell repertoire, known as education or licensing, is a complex process mediated through inhibitory receptors that recognize self. We found that NK cells containing self-killer Ig-like receptors for cognate HLA ligand in vivo were less susceptible to apoptosis. In vitro IL-15 withdrawal showed that uneducated NK cells upregulated Bim and Fas. Conversely, educated NK cells upregulated Fas ligand (FasL) under these conditions. Induction of cell death and Bim expression on uneducated cells correlated with increased IL-2Rα expression. Overexpression and knockdown studies showed that higher IL-2Rα limits NK cell survival in a novel manner that is independent from the role of IL-2 in activation-induced cell death. To study the role of FasL in induction of IL-2Rα(hi) NK cell death, a coculture assay with FasL-blocking Abs was used. IL-15 withdrawal led to FasL-dependent killing of IL-2Rα(hi) NK cells by more educated IL-2Rα(lo) NK cells. Finally, CMV reactivation induces a potent long-lasting population of licensed NK cells with enhanced survival. These findings show that education-dependent NK cell survival advantages and killing of uneducated NK cells result in the maintenance of a functional repertoire, which may be manipulated to exploit NK cells for cancer immunotherapy.
authors.affiliation: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Martin
authors.initials: M
authors.lastname: Felices
authors.forename: Todd R
authors.initials: TR
authors.lastname: Lenvik
authors.forename: Dave E M
authors.initials: DE
authors.lastname: Ankarlo
authors.forename: Bree
authors.initials: B
authors.lastname: Foley
authors.forename: Julie
authors.initials: J
authors.lastname: Curtsinger
authors.forename: Xianghua
authors.initials: X
authors.lastname: Luo
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Anderson
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002450:Cell Communication; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D003587:Cytomegalovirus / Q000502:physiology; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis; D006801:Humans; D019409:Interleukin-15 / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D054340:Receptors, KIR / Q000235:genetics / Q000378:metabolism; D014775:Virus Activation
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D053222:Fas Ligand Protein; D019409:Interleukin-15; D053645:Interleukin-2 Receptor alpha Subunit; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D054340:Receptors, KIR