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

Jin Sung Chung, Makoto Bonkobara, Mizuki Tomihari, Ponciano D Cruz, Kiyoshi Ariizumi

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

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-β. 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-β 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.

Original languageEnglish (US)
Pages (from-to)965-974
Number of pages10
JournalEuropean Journal of Immunology
Volume39
Issue number4
DOIs
StatePublished - 2009

Fingerprint

Syndecan-4
T-Lymphocytes
Monocytes
Heparin Lyase
Langerhans Cells
T-Cell Antigen Receptor
S Phase
Dendritic Cells
Serine
Tyrosine
Cell Cycle
Leukocytes
Cell Death
Cytokines
Ligands

Keywords

  • Antigen presenting cells
  • DC-HIL
  • Syndecan-4
  • T cells

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-cell responses. / Chung, Jin Sung; Bonkobara, Makoto; Tomihari, Mizuki; Cruz, Ponciano D; Ariizumi, Kiyoshi.

In: European Journal of Immunology, Vol. 39, No. 4, 2009, p. 965-974.

Research output: Contribution to journalArticle

Chung, Jin Sung ; Bonkobara, Makoto ; Tomihari, Mizuki ; Cruz, Ponciano D ; Ariizumi, Kiyoshi. / The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-cell responses. In: European Journal of Immunology. 2009 ; Vol. 39, No. 4. pp. 965-974.
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