Inhibition of T-cell activation by syndecan-4 is mediated by CD148 through protein tyrosine phosphatase activity

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Abstract

Most coinhibitory receptors regulate T-cell responses through an ITIM that recruits protein tyrosine phosphatases (PTPs) to mediate inhibitory function. Because syndecan-4 (SD-4), the coinhibitor for DC-associated heparan sulfate proteoglycan integrin ligand (DC-HIL), lacks such an ITIM, we posited that SD-4 links with a PTP in an ITIM-independent manner. We show that SD-4 associates constitutively with the intracellular protein syntenin but not with the receptor-like PTP CD148 on human CD4+ T cells. Binding to DC-HIL allowed SD-4 to assemble with CD148 through the help of syntenin as a bridge, and this process upregulated the PTP activity of CD148, which is required for SD-4 to mediate DC-HIL's inhibitory function. Using a mouse model, we found SD-4 to be located away from the immunological synapse formed between T cells and APCs during activation of T cells. These findings indicate that SD-4 is unique among known T-cell coinhibitors, in employing CD148 to inhibit T-cell activation at a site distal from the synapse.

Original languageEnglish (US)
Pages (from-to)1794-1799
Number of pages6
JournalEuropean Journal of Immunology
Volume41
Issue number6
DOIs
StatePublished - Jun 1 2011

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Keywords

  • CD148
  • Co-inhibitory receptors
  • DC-associated heparan sulfate proteoglycan integrin ligand (DC-HIL)
  • Syndecan-4
  • T cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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