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

2015; Rockefeller University Press; Volume: 211; Issue: 3 Linguagem: Inglês

10.1083/jcb.2113oia260

1540-8140

Mary J. van Helden, Steven Goossens, Cécile Daussy, Anne‐Laure Mathieu, Fabrice Faure, Antoine Marçais, Niels Vandamme, Natalie Farla, Katia Mayol, Sébastien Viel, Sophie Degouve, Emilie Debien, Eve Seuntjens, Andrea Conidi, Julie Chaix, Philippe Mangeot, Simon de Bernard, Laurent Buffat, Jody J. Haigh, Danny Huylebroeck, Bart N. Lambrecht, Geert Berx, Thierry Walzer,

CAR-T cell therapy research

NK cells are innate lymphocytes with important roles in the defense against intracellular pathogens and in cancer immunosurveillance.They have the capacity to recognize and kill target cells through a limited set of surface receptors and through the release of cytotoxic granules containing perforin and granzymes.NK cell development occurs mainly in the BM.After commitment to the NK cell lineage, NK cells undergo a maturation program (Huntington et al., 2007b).Three maturation intermediates can be defined on the basis of surface expression of CD27 and CD11b: CD11b -CD27 + NK cells (hereafter referred to as CD11b -, the most immature stage), CD11b + CD27 + (double positive [DP]), and CD-11b + CD27 -(CD27 -, the most mature subset), respectively (Kim et al., 2002;Hayakawa and Smyth, 2006).During maturation, NK cells progressively lose their capacity to proliferate, acquire the full set of NK cell receptors as well as cytotoxic arsenal, and modify their trafficking machinery.In particular, they acquire sphingosine-1 phosphate receptor 5 (S1PR5), which allows their egress from the BM and LNs and their circulation through the blood (Walzer et al., 2007;Mayol et al., 2011).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.