The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-cell responses

Eur J Immunol. 2009 Apr;39(4):965-74. doi: 10.1002/eji.200838990.


T-cell activation is regulated by binding of ligands on APC to corresponding receptors on T cells. In mice, we discovered that binding of DC-HIL on APC to syndecan-4 (SD-4) on activated T cells potently inhibits T-cell activation. In humans, we now show that DC-HIL also binds to SD-4 on activated T cells through recognition of its heparinase-sensitive saccharide moiety. DC-HIL blocks anti-CD3-induced T-cell responses, reducing secretion of pro-inflammatory cytokines and blocking entry into the S phase of the cell cycle. Binding of DC-HIL phosphorylates SD-4's intracellular tyrosine and serine residues. Anti-SD-4 Ab mimics the ability of DC-HIL to attenuate anti-CD3 response more potently than Ab directed against other inhibitory receptors (CTLA-4 or programmed cell death-1). Among leukocytes, DC-HIL is expressed highest by CD14(+) monocytes and this expression can be upregulated markedly by TGF-beta. Among APC, DC-HIL is expressed highest by epidermal Langerhans cells, an immature type of dendritic cells. Finally, the level of DC-HIL expression on CD14(+) monocytes correlates inversely with allostimulatory capacity, such that treatment with TGF-beta reduced this capacity, whereas knocking down the DC-HIL gene augmented it. Our findings indicate that the DC-HIL/SD-4 pathway can be manipulated to treat T-cell-driven disorders in humans.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • Cytokines / immunology
  • Cytokines / metabolism*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation / immunology
  • Membrane Glycoproteins / immunology
  • Membrane Glycoproteins / metabolism*
  • Monocytes / immunology
  • Monocytes / metabolism
  • Phosphorylation / immunology
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / metabolism*
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / metabolism
  • Syndecan-4 / immunology
  • Syndecan-4 / metabolism*
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • Transfection
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / metabolism


  • Cytokines
  • GPNMB protein, human
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Recombinant Fusion Proteins
  • Syndecan-4
  • Transforming Growth Factor beta