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

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...

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Veröffentlicht in:European journal of immunology 2009-04, Vol.39 (4), p.965-974
Hauptverfasser: Chung, Jin-Sung, Bonkobara, Makoto, Tomihari, Mizuki, Cruz, Ponciano D. Jr, Ariizumi, Kiyoshi
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Sprache:eng
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Zusammenfassung: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.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.200838990