Galectin-9-CD44 interaction enhances stability and function of adaptive regulatory T cells

Immunity. 2014 Aug 21;41(2):270-82. doi: 10.1016/j.immuni.2014.06.011. Epub 2014 Jul 24.

Abstract

The β-galactoside-binding protein galectin-9 is critical in regulating the immune response, but the mechanism by which it functions remains unclear. We have demonstrated that galectin-9 is highly expressed by induced regulatory T cells (iTreg) and was crucial for the generation and function of iTreg cells, but not natural regulatory T (nTreg) cells. Galectin-9 expression within iTreg cells was driven by the transcription factor Smad3, forming a feed-forward loop, which further promoted Foxp3 expression. Galectin-9 increased iTreg cell stability and function by directly binding to its receptor CD44, which formed a complex with transforming growth factor-β (TGF-β) receptor I (TGF-βRI), and activated Smad3. Galectin-9 signaling was further found to regulate iTreg cell induction by dominantly acting through the CNS1 region of the Foxp3 locus. Our data suggest that exogenous galectin-9, in addition to being an effector molecule for Treg cells, acts synergistically with TGF-β to enforce iTreg cell differentiation and maintenance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / immunology
  • Colitis / genetics
  • Colitis / immunology
  • Forkhead Transcription Factors / biosynthesis*
  • Galectins / genetics
  • Galectins / immunology*
  • Hepatitis A Virus Cellular Receptor 2
  • Hyaluronan Receptors / immunology*
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein-Serine-Threonine Kinases / immunology
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / immunology
  • Receptors, Virus / immunology
  • Signal Transduction / immunology
  • Smad3 Protein / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • Transforming Growth Factor beta / immunology

Substances

  • Cd44 protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Galectins
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Hyaluronan Receptors
  • LGALS9 protein, mouse
  • Receptors, Transforming Growth Factor beta
  • Receptors, Virus
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta
  • galectin 9, mouse
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I