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J Exp Med. 2015 Nov 16;212(12):2015-25. doi: 10.1084/jem.20150809. Epub 2015 Oct 26.

Terminal NK cell maturation is controlled by concerted actions of T-bet and Zeb2 and is essential for melanoma rejection.

Author information

1
Laboratory of Immunoregulation and Mucosal Immunology, VIB Inflammation Research Center, 9052 Ghent, Belgium GROUP-ID Consortium, Ghent University, 9000 Ghent, Belgium Department of Respiratory Medicine, Ghent University, 9052 Ghent, Belgium.
2
Unit of Molecular and Cellular Oncology, VIB Inflammation Research Center, 9052 Ghent, Belgium Department for Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
3
Université de Lyon, 69007 Lyon, France Institut National de la Santé et de la Recherche Médicale, U1111, 69342 Lyon, France Ecole Normale Supérieure de Lyon, 69007 Lyon, France Centre International de Recherche en Infectiologie, 69007 Lyon, France Centre National de la Recherche Scientifique, UMR5308, 69342 Lyon, France.
4
Université de Lyon, 69007 Lyon, France Institut National de la Santé et de la Recherche Médicale, U1111, 69342 Lyon, France Ecole Normale Supérieure de Lyon, 69007 Lyon, France Centre International de Recherche en Infectiologie, 69007 Lyon, France Centre National de la Recherche Scientifique, UMR5308, 69342 Lyon, France Laboratoire d'Immunologie, Hospices Civils de Lyon, 69495 Lyon, France.
5
Department for Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium Université de Lyon, 69007 Lyon, France Institut National de la Santé et de la Recherche Médicale, U1111, 69342 Lyon, France Ecole Normale Supérieure de Lyon, 69007 Lyon, France Centre International de Recherche en Infectiologie, 69007 Lyon, France.
6
Laboratory of Molecular Biology (Celgen), Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
7
Department of Cell Biology, Erasmus MC, 3015 CN Rotterdam, Netherlands.
8
Centre d'Immunologie de Marseille-Luminy, 13009 Marseille, France.
9
AltraBio SAS, 69007 Lyon, France.
10
Department for Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
11
Laboratory of Molecular Biology (Celgen), Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium Department of Cell Biology, Erasmus MC, 3015 CN Rotterdam, Netherlands.
12
Laboratory of Immunoregulation and Mucosal Immunology, VIB Inflammation Research Center, 9052 Ghent, Belgium GROUP-ID Consortium, Ghent University, 9000 Ghent, Belgium Department of Pulmonary Medicine, Erasmus MC, 3015 CN Rotterdam, Netherlands.
13
Université de Lyon, 69007 Lyon, France Institut National de la Santé et de la Recherche Médicale, U1111, 69342 Lyon, France Ecole Normale Supérieure de Lyon, 69007 Lyon, France Centre International de Recherche en Infectiologie, 69007 Lyon, France Centre National de la Recherche Scientifique, UMR5308, 69342 Lyon, France Thierry.walzer@inserm.fr.

Abstract

Natural killer (NK) cell maturation is a tightly controlled process that endows NK cells with functional competence and the capacity to recognize target cells. Here, we found that the transcription factor (TF) Zeb2 was the most highly induced TF during NK cell maturation. Zeb2 is known to control epithelial to mesenchymal transition, but its role in immune cells is mostly undefined. Targeted deletion of Zeb2 resulted in impaired NK cell maturation, survival, and exit from the bone marrow. NK cell function was preserved, but mice lacking Zeb2 in NK cells were more susceptible to B16 melanoma lung metastases. Reciprocally, ectopic expression of Zeb2 resulted in a higher frequency of mature NK cells in all organs. Moreover, the immature phenotype of Zeb2(-/-) NK cells closely resembled that of Tbx21(-/-) NK cells. This was caused by both a dependence of Zeb2 expression on T-bet and a probable cooperation of these factors in gene regulation. Transgenic expression of Zeb2 in Tbx21(-/-) NK cells partially restored a normal maturation, establishing that timely induction of Zeb2 by T-bet is an essential event during NK cell differentiation. Finally, this novel transcriptional cascade could also operate in human as T-bet and Zeb2 are similarly regulated in mouse and human NK cells.

PMID:
26503444
PMCID:
PMC4647267
DOI:
10.1084/jem.20150809
[Indexed for MEDLINE]
Free PMC Article

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