title: Transcription factor Foxo1 is a negative regulator of natural killer cell maturation and function.
abstract: Little is known about the role of negative regulators in controlling natural killer (NK) cell development and effector functions. Foxo1 is a multifunctional transcription factor of the forkhead family. Using a mouse model of conditional deletion in NK cells, we found that Foxo1 negatively controlled NK cell differentiation and function. Immature NK cells expressed abundant Foxo1 and little Tbx21 relative to mature NK cells, but these two transcription factors reversed their expression as NK cells proceeded through development. Foxo1 promoted NK cell homing to lymph nodes by upregulating CD62L expression and inhibited late-stage maturation and effector functions by repressing Tbx21 expression. Loss of Foxo1 rescued the defect in late-stage NK cell maturation in heterozygous Tbx21(+/-) mice. Collectively, our data reveal a regulatory pathway by which the negative regulator Foxo1 and the positive regulator Tbx21 play opposing roles in controlling NK cell development and effector functions.
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210, USA; Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Youcai
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University UM2, Inserm U1104, CNRS UMR7280, Marseille 13288, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Kerdiles
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Chu
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; Department of Lymphoma, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China.
authors.forename: Shunzong
authors.initials: S
authors.lastname: Yuan
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Youwei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; Department of Lymphoma, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China.
authors.forename: Xilin
authors.initials: X
authors.lastname: Chen
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Hsiaoyin
authors.initials: H
authors.lastname: Mao
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Hughes
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Fangjie
authors.initials: F
authors.lastname: Wang
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Zou
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Chang-Gong
authors.initials: CG
authors.lastname: Liu
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Aharon G
authors.initials: AG
authors.lastname: Freud
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; The James Cancer Hospital, The Ohio State University, Columbus, OH 43210, USA. Electronic address: michael.caligiuri@osumc.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University UM2, Inserm U1104, CNRS UMR7280, Marseille 13288, France; Service d'Immunologie, Assistance Publique - Hôpitaux de Marseille, Marseille 13385, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; The James Cancer Hospital, The Ohio State University, Columbus, OH 43210, USA. Electronic address: jianhua.yu@osumc.edu.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic; D006579:Heterozygote; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D019041:L-Selectin / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000276:immunology / Q000556:secondary; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008212:Lymphocyte Depletion; D008546:Melanoma, Experimental / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000276:immunology / Q000556:secondary; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D019041:L-Selectin