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

Nat Immunol. 2017 Sep;18(9):995-1003. doi: 10.1038/ni.3809. Epub 2017 Jul 31.

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.

MeSH terms

  • Adenomatous Polyposis Coli / genetics
  • Adenomatous Polyposis Coli / immunology
  • Animals
  • Case-Control Studies
  • Cell Differentiation
  • Gene Expression Profiling
  • Humans
  • Immunity, Innate / immunology
  • Immunoblotting
  • Immunologic Deficiency Syndromes / genetics
  • Immunologic Deficiency Syndromes / immunology
  • Killer Cells, Natural / cytology*
  • Lymphocytes / cytology
  • Lymphopoiesis / genetics*
  • Melanoma, Experimental / immunology
  • Mice
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / immunology
  • Smad4 Protein / genetics*
  • Smad4 Protein / immunology
  • Transforming Growth Factor beta / immunology*

Substances

  • SMAD4 protein, human
  • Smad4 Protein
  • Smad4 protein, mouse
  • Transforming Growth Factor beta