Terminal NK cell maturation is controlled by concerted actions of T-bet and Zeb2 and is essential for melanoma rejection.
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.
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.
Mary J
MJ
van Helden
Unit of Molecular and Cellular Oncology, VIB Inflammation Research Center, 9052 Ghent, Belgium Department for Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
Steven
S
Goossens
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.
Cécile
C
Daussy
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.
Anne-Laure
AL
Mathieu
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.
Fabrice
F
Faure
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.
Antoine
A
Marçais
Unit of Molecular and Cellular Oncology, VIB Inflammation Research Center, 9052 Ghent, Belgium Department for Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
Niels
N
Vandamme
Unit of Molecular and Cellular Oncology, VIB Inflammation Research Center, 9052 Ghent, Belgium Department for Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
Natalie
N
Farla
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.
Katia
K
Mayol
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.
Sébastien
S
Viel
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.
Sophie
S
Degouve
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.
Emilie
E
Debien
Laboratory of Molecular Biology (Celgen), Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
Eve
E
Seuntjens
Department of Cell Biology, Erasmus MC, 3015 CN Rotterdam, Netherlands.
Andrea
A
Conidi
Centre d'Immunologie de Marseille-Luminy, 13009 Marseille, France.
Julie
J
Chaix
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.
Philippe
P
Mangeot
AltraBio SAS, 69007 Lyon, France.
Simon
S
de Bernard
AltraBio SAS, 69007 Lyon, France.
Laurent
L
Buffat
Department for Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
Jody J
JJ
Haigh
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.
Danny
D
Huylebroeck
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.
Bart N
BN
Lambrecht
Unit of Molecular and Cellular Oncology, VIB Inflammation Research Center, 9052 Ghent, Belgium Department for Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
Geert
G
Berx
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.
Thierry
T
Walzer
D000818:Animals; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2; D000098815:T-bet Transcription Factor
D016207:Cytokines; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2