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

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.

• Authors: Jin-Sung Chung, Mizuki Tomihari, Kyoichi Tamura, Tetsuhito Kojima, Ponciano D Cruz Jr, Kiyoshi Ariizumi
• Journal: Immunology (Immunology) Vol. 138 Issue 2 Pg. 173-82 (Feb 2013) ISSN: 1365-2567 [Electronic] England
• PMID: 23113638 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

Chemical References

• Eye Proteins
• Gpnmb protein, mouse
• Membrane Glycoproteins
• Receptors, Immunologic
• Sdc4 protein, mouse
• Syndecan-4

Topics

• Acute Disease
• Animals
• Eye Proteins
• Graft vs Host Disease (genetics, immunology, pathology, therapy)
• Hematopoietic Stem Cell Transplantation
• Membrane Glycoproteins (agonists, genetics, immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Receptors, Immunologic (agonists, genetics, immunology)
• Syndecan-4 (genetics, immunology)
• T-Lymphocytes, Regulatory (immunology, pathology)
• Transplantation, Homologous