期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 212, 期 12, 页码 2015-2025出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20150809
关键词
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资金
- FINOVI foundation
- Agence Nationale de la Recherche
- European Research council [ERC-Stg 281025]
- INSERM
- CNRS
- Universite de Lyon
- ENS de Lyon
- FWO-V [G.0529.12N, G.0954.11N]
- geconcerteerde onderzoeksacties UGent [GOA-01GB1013W]
- Belgian Federation for the Study Against Cancer
- ERC
- Interuniversity Attraction Poles [IUAP-VII/03]
- Research Council of KU Leuven [GOA-11/012]
- Queen Elisabeth Medical Foundation [GSKE 1113]
- Erasmus MC start-up funds
- Belgium Federation against Cancer
- FWO
- IUAP
- National Health and Medical Research Council
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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