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Terminal NK cell maturation is controlled by concerted actions of T-bet and Zeb2
and is essential for melanoma rejection
#MMPMID26503444
van Helden MJ
; Goossens S
; Daussy C
; Mathieu AL
; Faure F
; Marçais A
; Vandamme N
; Farla N
; Mayol K
; Viel S
; Degouve S
; Debien E
; Seuntjens E
; Conidi A
; Chaix J
; Mangeot P
; de Bernard S
; Buffat L
; Haigh JJ
; Huylebroeck D
; Lambrecht BN
; Berx G
; Walzer T
J Exp Med
2015[Nov]; 212
(12
): 2015-25
PMID26503444
show ga
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.
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