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Transcription Factor Foxo1 Is a Negative Regulator of Natural Killer Cell Maturation and Function

Significance Statement

The collaborative research team at Ohio State University Cancer Centre discovered a pathway that cancer cells may use to block NK-cell function and evade immune responses. Foxo1 was shown to exert its inhibitory effects by blocking transcription of the gene that encodes Tbx21, which is a positive regulator of NK-cell development and function. The findings could lead to new strategies for boosting natural-killer cell activity against cancer and viral infections by reducing Foxo1 expression.

 

Transcription Factor Foxo1 Is a Negative Regulator of Natural Killer Cell Maturation and Function.-	. Global Medical Discovery

 

 

 

 

 

 

Journal Reference

Deng Y1, Kerdiles Y2, Chu J3, Yuan S4, Wang Y3, Chen X4, Mao H3, Zhang L3, Zhang J5, Hughes T3, Deng Y6,Zhang Q6, Wang F6, Zou X3, Liu CG7, Freud AG3, Li X6, Caligiuri MA8, Vivier E9, Yu J10. Immunity. 2015 Mar 17;42(3):457-70.

Show Affiliations

1Division 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.

2Centre d’Immunologie de Marseille-Luminy, Aix-Marseille University UM2, Inserm U1104, CNRS UMR7280, Marseille 13288, France.

3The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.

4The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; Department of Lymphoma, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China.

5Center for Biostatistics, The Ohio State University, Columbus, OH 43210, USA.

6Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.

7Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

8Division 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: [email protected]

9Centre 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.

10Division 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: [email protected]

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 fork head 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 NKcell development and effector functions.

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