title: IL-15 trans-presentation promotes human NK cell development and differentiation in vivo.
abstract: The in vivo requirements for human natural killer (NK) cell development and differentiation into cytotoxic effectors expressing inhibitory receptors for self-major histocompatibility complex class I (MHC-I; killer Ig-like receptors [KIRs]) remain undefined. Here, we dissect the role of interleukin (IL)-15 in human NK cell development using Rag2(-/-)gamma c(-/-) mice transplanted with human hematopoietic stem cells. Human NK cell reconstitution was intrinsically low in this model because of the poor reactivity to mouse IL-15. Although exogenous human IL-15 (hIL-15) alone made little improvement, IL-15 coupled to IL-15 receptor alpha (IL-15R alpha) significantly augmented human NK cells. IL-15-IL-15R alpha complexes induced extensive NK cell proliferation and differentiation, resulting in accumulation of CD16(+)KIR(+) NK cells, which was not uniquely dependent on enhanced survival or preferential responsiveness of this subset to IL-15. Human NK cell differentiation in vivo required hIL-15 and progressed in a linear fashion from CD56(hi)CD16(-)KIR(-) to CD56(lo)CD16(+)KIR(-), and finally to CD56(lo)CD16(+)KIR(+). These data provide the first evidence that IL-15 trans-presentation regulates human NK cell homeostasis. Use of hIL-15 receptor agonists generates a robust humanized immune system model to study human NK cells in vivo. IL-15 receptor agonists may provide therapeutic tools to improve NK cell reconstitution after bone marrow transplants, enhance graft versus leukemia effects, and increase the pool of IL-15-responsive cells during immunotherapy strategies.
authors.affiliation: Immunology Department, 2 Institut National de la Santé et de la Recherche Médicale U668, 3 INSERM U883, Unité de Régulation Immunitaire et Vaccinologie, Institut Pasteur, Paris 75724, France. nhunting@pasteur.fr
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Huntington
authors.forename: Nicolas
authors.initials: N
authors.lastname: Legrand
authors.forename: Nuno L
authors.initials: NL
authors.lastname: Alves
authors.forename: Barbara
authors.initials: B
authors.lastname: Jaron
authors.forename: Kees
authors.initials: K
authors.lastname: Weijer
authors.forename: Ariane
authors.initials: A
authors.lastname: Plet
authors.forename: Erwan
authors.initials: E
authors.lastname: Corcuff
authors.forename: Erwan
authors.initials: E
authors.lastname: Mortier
authors.forename: Yannick
authors.initials: Y
authors.lastname: Jacques
authors.forename: Hergen
authors.initials: H
authors.lastname: Spits
authors.forename: James P
authors.initials: JP
authors.lastname: Di Santo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000943:Antigens, Differentiation / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D019409:Interleukin-15 / Q000008:administration & dosage / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008221:Lymphoid Tissue / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D053647:Receptors, Interleukin-15 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; C508024:IL15RA protein, human; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15; C499308:Rag2 protein, mouse; D053647:Receptors, Interleukin-15; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein