Transforming Growth Factor-β Signaling Guides the Differentiation of Innate Lymphoid Cells in Salivary Glands

Immunity. 2016 May 17;44(5):1127-39. doi: 10.1016/j.immuni.2016.03.007. Epub 2016 May 3.


The signals guiding differentiation of innate lymphoid cells (ILCs) within tissues are not well understood. Salivary gland (SG) ILCs as well as liver and intestinal intraepithelial ILC1 have markers that denote tissue residency and transforming growth factor-β (TGF-β) imprinting. We deleted Tgfbr2 in cells expressing the ILC and NK marker NKp46 and found that SG ILCs were reduced in number. They lost distinct tissue markers, such as CD49a, and the effector molecules TRAIL and CD73. Expression of the transcription factor Eomes, which promotes NK cell differentiation, was elevated. Conversely, Eomes deletion in NKp46(+) cells enhanced TGF-β-imprinting of SG ILCs. Thus, TGF-β induces SG ILC differentiation by suppressing Eomes. TGF-β acted through a JNK-dependent, Smad4-independent pathway. Transcriptome analysis demonstrated that SG ILCs had characteristic of both NK cells and ILC1. Finally, TGF-β imprinting of SG ILCs was synchronized with SG development, highlighting the impact of tissue microenvironment on ILC development.

Keywords: TGF-β; development; innate lymphoid cells; salivary gland; signaling; transcription factors.

MeSH terms

  • Animals
  • Antigens, Ly / metabolism
  • Cell Differentiation*
  • Cellular Microenvironment
  • Gene Expression Profiling
  • Immunity, Innate
  • Killer Cells, Natural / physiology*
  • Lymphocytes / physiology*
  • MAP Kinase Kinase 4 / metabolism
  • Mice
  • Mice, Knockout
  • Natural Cytotoxicity Triggering Receptor 1 / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Salivary Glands / immunology*
  • Signal Transduction
  • Smad4 Protein / genetics
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism
  • Transforming Growth Factor beta / metabolism*


  • Antigens, Ly
  • Eomes protein, mouse
  • Natural Cytotoxicity Triggering Receptor 1
  • Ncr1 protein, mouse
  • Receptors, Transforming Growth Factor beta
  • Smad4 Protein
  • Smad4 protein, mouse
  • T-Box Domain Proteins
  • Transforming Growth Factor beta
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • MAP Kinase Kinase 4