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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow / immunology
  • Bone Marrow / metabolism
  • Cell Line, Tumor
  • Cell Survival / genetics
  • Cell Survival / immunology
  • Cells, Cultured
  • Cytokines / immunology
  • Cytokines / metabolism
  • Flow Cytometry
  • Gene Expression / immunology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / immunology*
  • Homeodomain Proteins / metabolism
  • Humans
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Repressor Proteins / genetics
  • Repressor Proteins / immunology*
  • Repressor Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / immunology*
  • T-Box Domain Proteins / metabolism
  • Zinc Finger E-box Binding Homeobox 2

Substances

  • Cytokines
  • Homeodomain Proteins
  • Repressor Proteins
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • ZEB2 protein, mouse
  • Zinc Finger E-box Binding Homeobox 2