SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-β signaling

VS Cortez, TK Ulland, L Cervantes-Barragan… - Nature …, 2017 - nature.com
Nature immunology, 2017nature.com
Among the features that distinguish type 1 innate lymphoid cells (ILC1s) from natural killer
(NK) cells is a gene signature indicative of'imprinting'by cytokines of the TGF-β family. We
studied mice in which ILC1s and NK cells lacked SMAD4, a signal transducer that facilitates
the canonical signaling pathway common to all cytokines of the TGF-β family. While SMAD4
deficiency did not affect ILC1 differentiation, NK cells unexpectedly acquired an ILC1-like
gene signature and were unable to control tumor metastasis or viral infection …
Abstract
Among the features that distinguish type 1 innate lymphoid cells (ILC1s) from natural killer (NK) cells is a gene signature indicative of 'imprinting' by cytokines of the TGF-β family. We studied mice in which ILC1s and NK cells lacked SMAD4, a signal transducer that facilitates the canonical signaling pathway common to all cytokines of the TGF-β family. While SMAD4 deficiency did not affect ILC1 differentiation, NK cells unexpectedly acquired an ILC1-like gene signature and were unable to control tumor metastasis or viral infection. Mechanistically, SMAD4 restrained non-canonical TGF-β signaling mediated by the cytokine receptor TGFβR1 in NK cells. NK cells from a SMAD4-deficient person affected by polyposis were also hyper-responsive to TGF-β. These results identify SMAD4 as a previously unknown regulator that restricts non-canonical TGF-β signaling in NK cells.
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