The DC-HIL ligand syndecan-4 is a negative regulator of T-cell allo-reactivity responsible for graft-versus-host disease

Jin Sung Chung, Mizuki Tomihari, Kyoichi Tamura, Tetsuhito Kojima, Ponciano D Cruz, Kiyoshi Ariizumi

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Acute graft-versus-host disease (GVHD) is the most important cause of mortality after allogeneic haematopoietic stem cell transplantation. Allo-reactive T cells are the major mediators of GVHD and the process is regulated by positive and negative regulators on antigen-presenting cells (APC). Because the significance of negative regulators in GVHD pathogenesis is not fully understood, and having discovered that syndecan-4 (SD-4) on effector T cells mediates the inhibitory function of DC-HIL on APC, we proposed that SD-4 negatively regulates the T-cell response to allo-stimulation in acute GVHD, using SD-4 knockout mice. Although not different from their wild-type counterparts in responsiveness to anti-CD3 stimulation, SD-4-/- T cells lost the capacity to mediate the inhibitory function of DC-HIL and were hyper-reactive to allogeneic APC. Moreover, infusion of SD-4-/- T cells into sub-lethally γ-irradiated allogeneic mice worsened mortality, with hyper-proliferation of infused T cells in recipients. Although there my be little or no involvement of regulatory T cells in this model because SD-4 deletion had no deleterious effect on T-cell-suppressive activity compared with SD-4+/+ regulatory T cells. We conclude that SD-4, as the T-cell ligand of DC-HIL, is a potent inhibitor of allo-reactive T cells responsible for GVHD and a potentially useful target for treating this disease. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

Original languageEnglish (US)
Pages (from-to)173-182
Number of pages10
JournalImmunology
Volume138
Issue number2
DOIs
StatePublished - Feb 1 2013

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Keywords

  • Co-inhibitory receptor
  • DC-HIL
  • Graft-versus-host disease
  • Syndecan-4
  • T-cell activation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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