title: 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.affiliation: Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Chung
authors.forename: Mizuki
authors.initials: M
authors.lastname: Tomihari
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Tamura
authors.forename: Tetsuhito
authors.initials: T
authors.lastname: Kojima
authors.forename: Ponciano D
authors.initials: PD
authors.lastname: Cruz
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ariizumi
mesh_terms: D000208:Acute Disease; D000818:Animals; D005136:Eye Proteins; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D008562:Membrane Glycoproteins / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D053671:Syndecan-4 / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D014184:Transplantation, Homologous
chemical_list: D005136:Eye Proteins; C445671:Gpnmb protein, mouse; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C508306:Sdc4 protein, mouse; D053671:Syndecan-4