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

被引：143

作者：

van Helden, Mary J. ^{[1
,3
,4
]}

Goossens, Steven ^{[2
,5
]}

Daussy, Cecile ^{[6
,7
,8
,9
,10
]}

Mathieu, Anne-Laure ^{[6
,7
,8
,9
,10
]}

Faure, Fabrice ^{[6
,7
,8
,9
,10
]}

Marcais, Antoine ^{[6
,7
,8
,9
,10
]}

Vandamme, Niels ^{[2
,5
]}

Farla, Natalie ^{[2
,5
]}

Mayol, Katia ^{[6
,7
,8
,9
,10
]}

Viel, Sebastien ^{[6
,7
,8
,9
,10
,11
]}

Degouve, Sophie ^{[5
,6
,7
,8
,9
]}

Debien, Emilie ^{[6
,7
,8
,9
,10
]}

Seuntjens, Eve ^{[12
]}

Conidi, Andrea ^{[13
]}

Chaix, Julie ^{[15
]}

Mangeot, Philippe ^{[6
,7
,8
,9
,10
]}

de Bernard, Simon ^{[16
]}

Buffat, Laurent ^{[16
]}

Haigh, Jody J. ^{[5
,17
]}

Huylebroeck, Danny ^{[12
,13
]}

Lambrecht, Bart N. ^{[1
,3
,14
]}

Berx, Geert ^{[2
,5
]}

Walzer, Thierry ^{[6
,7
,8
,9
,10
]}

机构：

[1] VIB Inflammat Res Ctr, Lab Immunoregulat & Mucosal Immunol, B-9052 Ghent, Belgium

[2] VIB Inflammat Res Ctr, Unit Mol & Cellular Oncol, B-9052 Ghent, Belgium

[3] Univ Ghent, GRP ID Consortium, B-9000 Ghent, Belgium

[4] Univ Ghent, Dept Resp Med, B-9052 Ghent, Belgium

[5] Univ Ghent, Dept Biomed Mol Biol, B-9052 Ghent, Belgium

[6] Univ Lyon, F-69007 Lyon, France

[7] INSERM, U1111, F-69342 Lyon, France

[8] Ecole Normale Super Lyon, F-69007 Lyon, France

[9] Ctr Int Rech Infectiol, F-69007 Lyon, France

[10] CNRS, UMR5308, F-69342 Lyon, France

[11] Hosp Civils Lyon, Lab Immunol, F-69495 Lyon, France

[12] Katholieke Univ Leuven, Dept Dev & Regenerat, Lab Mol Biol Celgen, B-3000 Leuven, Belgium

[13] Erasmus MC, Dept Cell Biol, NL-3015 CN Rotterdam, Netherlands

[14] Erasmus MC, Dept Pulm Med, NL-3015 CN Rotterdam, Netherlands

[15] Ctr Immunol Marseille Luminy, F-13009 Marseille, France

[16] AltraBio SAS, F-69007 Lyon, France

[17] Monash Univ, Australian Ctr Blood Dis, Melbourne, Vic 3004, Australia

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2015年 / 212卷 / 12期

基金：

英国医学研究理事会; 欧洲研究理事会;

关键词：

IN-VIVO; MOUSE; TRAFFICKING; HOMEOSTASIS; EXPRESSION; PROTEINS; RECEPTOR; DISEASE; MICE;

D O I：

10.1084/jem.20150809

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：2015 / 2025

页数：11

共 25 条

[11] Developmental pathways that generate natural-killer-cell diversity in mice and humans [J].