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

Chung, Jane; Bonkobara, Makoto; Tomihari, Mizuki; Cruz, Ponciano D.; Ariizumi, Kiyoshi

doi:10.1002/eji.200838990

Cited by 63 publications

(74 citation statements)

References 38 publications

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“…Having shown that DC-HIL acts as a PRR for dermatophytes and that epidermal LC express DC-HIL constitutively at high levels (human LC also express DC-HIL at high levels; Ref. 34), we posit that DC-HIL exerts antifungal immunity via innate immune recognition and potentiation of LC function. Concurrently, DC-HIL may suppress cutaneous inflammation by attenuating activity of T cells that home to skin.…”

Section: Discussionmentioning

confidence: 90%

Binding of DC-HIL to Dermatophytic Fungi Induces Tyrosine Phosphorylation and Potentiates Antigen Presenting Cell Function

Chung

Yudate

Tomihari

et al. 2009

The Journal of Immunology

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APCs express receptors recognizing microbes and regulating immune responses by binding to corresponding ligands on immune cells. Having discovered a novel inhibitory pathway triggered by ligation of DC-HIL on APC to a heparin/heparan sulfate-like saccharide of syndecan-4 on activated T cells, we posited DC-HIL can recognize microbial pathogens in a similar manner. We showed soluble recombinant DC-HIL to bind the dermatophytes Trichophyton rubrum and Microsporum audouinii, but not several bacteria nor Candida albicans. Dermatophyte binding was inhibited completely by the addition of heparin. Because DC-HIL contains an ITAM-like intracellular sequence, we questioned whether its binding to dermatophytes can induce tyrosine phosphorylation in dendritic cells (DC). Culturing DC with T. rubrum (but not with C. albicans pseudohyphae) induced phosphorylation of DC-HIL, but not when the tyrosine residue of the ITAM-like sequence was mutated to phenylalanine. To examine the functional significance of such signaling on DC, we cross-linked DC-HIL with mAb (surrogate ligand), which not only induced tyrosine phosphorylation but also up-regulated expression of 23 genes among 662 genes analyzed by gene-array, including genes for profilin-1, myristoylated alanine rich protein kinase C substrate like-1, C/EBP, LOX-1, IL-1β, and TNF-α. This cross-linking also up-regulated expression of the activation markers CD80/CD86 and heightened APC capacity of DC to activate syngeneic T cells. Our findings support a dual role for DC-HIL: inhibition of adaptive immunity following ligation of syndecan-4 on activated T cells and induction of innate immunity against dermatophytic fungi.

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Section: Discussionmentioning

confidence: 90%

Binding of DC-HIL to Dermatophytic Fungi Induces Tyrosine Phosphorylation and Potentiates Antigen Presenting Cell Function

Chung

Yudate

Tomihari

et al. 2009

The Journal of Immunology

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“…Recently, binding of DC-HIL to syndecan-4 on activated T cells was shown to inhibit human allogeneic T cell responses (32). In addition, syndecans have been shown to regulate TGF-␤ activity and to prevent toxic shock by their ability to suppress the production of proinflammatory cytokines by macrophages (45,46).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been shown that human resting CD4 ϩ T cells express low levels of syndecans on their cell surface, but upon activation the levels of syndecan-1 and -4 are significantly increased (32). Therefore, we tested whether PSG1 binding to CD4 ϩ T cells activated with plate-bound anti-CD3 differs from binding to nonactivated cells.…”

Section: Psg1 Binds To Cell Surface Proteoglycans-several Cell Typesmentioning

confidence: 99%

Pregnancy-specific Glycoprotein 1 Induces Endothelial Tubulogenesis through Interaction with Cell Surface Proteoglycans

Lisboa

Warren

Sulkowski

et al. 2011

Journal of Biological Chemistry

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Pregnancy-specific ␤1 glycoproteins (PSGs) are the most abundant fetal proteins in the maternal bloodstream in late pregnancy. They are secreted by the syncytiotrophoblast and are detected around day 14 postfertilization. There are 11 human PSG genes, which encode a family of proteins exhibiting significant conservation at the amino acid level. We and others have proposed that PSGs have an immune modulatory function. In addition, we recently postulated that they are proangiogenic due to their ability to induce the secretion of VEGF-A and the formation of tubes by endothelial cells. The cellular receptor(s) for human PSGs remain unknown. Therefore, we conducted these studies to identify the receptor for PSG1, the highest expressed member of the family. We show that removal of cell surface glycosaminoglycans (GAGs) by enzymatic or chemical treatment of cells or competition with heparin completely inhibited binding of PSG1. In addition, PSG1 did not bind to cells lacking heparan or chondroitin sulfate on their surface, and binding was restored upon transfection with all four syndecans and glypican-1. Importantly, the presence of GAGs on the surface of endothelial cells was required for the ability of PSG1 to induce tube formation. This finding indicates that the PSG1-GAG interaction mediates at least some of the PSG1 proposed functions.Pregnancy success requires that the maternal immune system does not attack the fetal trophoblast cells, which are in direct contact with maternal blood and express genes derived from both the mother and the father. In addition, during pregnancy major vascular adaptations are required to guarantee fetal growth and survival. These include uterine vessel dilation, remodeling of the maternal decidual arteries, and angiogenesis within the placenta villi, as reviewed in Ref.

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“…Tomilari et al found that Gpnmb/OA knockdown markedly reduced the growth of B16F10 melanoma cells in vivo following their s.c. injection into synogeneic immunocompetent mice. Gpnmb/OA was capable of suppressing the activation of T-cell activation, by binding to syndecan-4 and on the surface of activated T cells and inducing its auto-phosphorylation, thereby allowing melanoma to evade immunologic recognition and destruction [28][29][30][31][32]. (3) By decreasing apoptosis and increasing vascular density.…”

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confidence: 99%

Gpnmb/osteoactivin, an attractive target in cancer immunotherapy

Zhou¹,

Liu²,

Li³

et al. 2012

neo

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Cancer is a complex disease with interactions between normal and neoplastic cells. Since current therapies for cancer largely rely on drugs or radiation that kill dividing cells or block cell division, these treatments may have severe side effects on normal proliferating cells in patients with cancer. Recently, immunotherapeutic approaches for cancer therapy, by which monoclonal antibodies (Mabs) target tumor specific antigens, have shown great potential. Glycoprotein non-metastatic melanoma protein B (Gpnmb)/Osteoactivin (OA) is a transmembrane glycoprotein highly expressed in various types of cancer. Gpnmb/OA promotes the migration, invasion and metastasis of tumor cells. CR 011-vcMMAE is a Mab-drug conjugate being developed for the treatment of Gpnmb/OA-expressing cancers. Gpnmb/OA represents an attractive target in cancer immunotherapy and CR011-vcMMAE holds promise as a reagent in targeted therapy for Gpnmb/OA-expressing malignancies.

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

Cited by 63 publications

References 38 publications

Binding of DC-HIL to Dermatophytic Fungi Induces Tyrosine Phosphorylation and Potentiates Antigen Presenting Cell Function

Binding of DC-HIL to Dermatophytic Fungi Induces Tyrosine Phosphorylation and Potentiates Antigen Presenting Cell Function

Pregnancy-specific Glycoprotein 1 Induces Endothelial Tubulogenesis through Interaction with Cell Surface Proteoglycans

Gpnmb/osteoactivin, an attractive target in cancer immunotherapy

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