title: Activating Receptor Signals Drive Receptor Diversity in Developing Natural Killer Cells.
abstract: It has recently been appreciated that NK cells exhibit many features reminiscent of adaptive immune cells. Considerable heterogeneity exists with respect to the ligand specificity of individual NK cells and as such, a subset of NK cells can respond, expand, and differentiate into memory-like cells in a ligand-specific manner. MHC I-binding inhibitory receptors, including those belonging to the Ly49 and KIR families, are expressed in a variegated manner, which creates ligand-specific diversity within the NK cell pool. However, how NK cells determine which inhibitory receptors to express on their cell surface during a narrow window of development is largely unknown. In this manuscript, we demonstrate that signals from activating receptors are critical for induction of Ly49 and KIR receptors during NK cell development; activating receptor-derived signals increased the probability of the Ly49 bidirectional Pro1 promoter to transcribe in the forward versus the reverse direction, leading to stable expression of Ly49 receptors in mature NK cells. Our data support a model where the balance of activating and inhibitory receptor signaling in NK cells selects for the induction of appropriate inhibitory receptors during development, which NK cells use to create a diverse pool of ligand-specific NK cells.
authors: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors: Jacquelyn
authors: J
authors: Freund
authors: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors: Rebecca M
authors: RM
authors: May
authors: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors: Enjun
authors: 0000-0003-1511-7511
authors: E
authors: Yang
authors: Basic Science Program, Leidos Biomedical Research Inc., Frederick National Lab, Frederick, Maryland, United States of America.
authors: Hongchuan
authors: H
authors: Li
authors: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors: Matthew
authors: M
authors: McCullen
authors: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors: Bin
authors: B
authors: Zhang
authors: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors: Todd
authors: T
authors: Lenvik
authors: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors: Frank
authors: F
authors: Cichocki
authors: Basic Science Program, Leidos Biomedical Research Inc., Frederick National Lab, Frederick, Maryland, United States of America.|Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors: Stephen K
authors: SK
authors: Anderson
authors: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors: Taku
authors: T
authors: Kambayashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D005434:Flow Cytometry; D014644:Genetic Variation / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference; D054340:Receptors, KIR / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D055650:NK Cell Lectin-Like Receptor Subfamily A; D010750:Phosphoproteins; D054340:Receptors, KIR; C092947:SLP-76 signal Transducing adaptor proteins