Cell surface galectin-9 expressing Th cells regulate Th17 and Foxp3+ Treg development by galectin-9 secretion

PLoS One. 2012;7(11):e48574. doi: 10.1371/journal.pone.0048574. Epub 2012 Nov 7.

Abstract

Galectin-9 (Gal-9), a β-galactoside binding mammalian lectin, regulates immune responses by reducing pro-inflammatory IL-17-producing Th cells (Th17) and increasing anti-inflammatory Foxp3(+) regulatory T cells (Treg) in vitro and in vivo. These functions of Gal-9 are thought to be exerted by binding to receptor molecules on the cell surface. However, Gal-9 lacks a signal peptide for secretion and is predominantly located in the cytoplasm, which raises questions regarding how and which cells secrete Gal-9 in vivo. Since Gal-9 expression does not necessarily correlate with its secretion, Gal-9-secreting cells in vivo have been elusive. We report here that CD4 T cells expressing Gal-9 on the cell surface (Gal-9(+) Th cells) secrete Gal-9 upon T cell receptor (TCR) stimulation, but other CD4 T cells do not, although they express an equivalent amount of intracellular Gal-9. Gal-9(+) Th cells expressed interleukin (IL)-10 and transforming growth factor (TGF)-β but did not express Foxp3. In a co-culture experiment, Gal-9(+) Th cells regulated Th17/Treg development in a manner similar to that by exogenous Gal-9, during which the regulation by Gal-9(+) Th cells was shown to be sensitive to a Gal-9 antagonist but insensitive to IL-10 and TGF-β blockades. Further elucidation of Gal-9(+) Th cells in humans indicates a conserved role of these cells through evolution and implies the possible utility of these cells for diagnosis or treatment of immunological diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / metabolism*
  • Forkhead Transcription Factors / metabolism*
  • Galectins / metabolism*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Phenotype
  • Receptors, Antigen, T-Cell
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / metabolism
  • Th17 Cells / cytology*
  • Th17 Cells / metabolism

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Galectins
  • LGALS9 protein, human
  • Receptors, Antigen, T-Cell
  • galectin 9, mouse

Grant support

This work was supported by a Grant-In-Aid for young scientists (B) 2008–2009 (20790570) from the Japan Society for Promotion of Science (JSPS), Scientific Research (C) 2010- (22590360) from JSPS, Scientific Research (C) 2011- (23591438) from JSPS, Scientific Research (A) 2011- (23256004) from JSPS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. (JSPS HP: http://www.jsps.go.jp/). No additional external funding was received for this study.