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Immunity. 2015 Mar 17;42(3):457-70. doi: 10.1016/j.immuni.2015.02.006. Epub 2015 Mar 10.

Transcription factor Foxo1 is a negative regulator of natural killer cell maturation and function.

Author information

1
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.
2
Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University UM2, Inserm U1104, CNRS UMR7280, Marseille 13288, France.
3
The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
4
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.
5
Center for Biostatistics, The Ohio State University, Columbus, OH 43210, USA.
6
Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
7
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
8
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.
9
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.
10
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.

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.

PMID:
25769609
PMCID:
PMC4400836
DOI:
10.1016/j.immuni.2015.02.006
[Indexed for MEDLINE]
Free PMC Article

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