title: Synthesis and surface expression of hyaluronan by dendritic cells and its potential role in antigen presentation.
abstract: Hyaluronan (HA) is a large glycosaminoglycan consisting of repeating disaccharide units of glucuronic acid and N-acetylglucosamine. HA is known to act as a filling material of extracellular matrices and as an adhesive substrate for cellular migration. Here we report that dendritic cells (DC) express mRNAs for HA synthases and hyaluronidases, actively synthesize HA, and display HA on their surfaces. Interestingly, HA expression levels on DC were not significantly altered by their maturation states. With respect to physiological function, three specific HA inhibitors, i.e., bovine proteoglycan, a 12-mer HA-binding peptide (GAHWQFNALTVR) termed Pep-1, and an oligomeric Pep-1 formulation, all interfered with DC-induced activation of CD4(+) T cells isolated from DO11.10 TCR transgenic mice. For example, Pep-1 oligomer efficiently inhibited DC-dependent cluster formation, IL-2 and IFN-gamma production, and proliferation by DO11.10 T cells in vitro without affecting the viabilities of DC or T cells, DC function to uptake exogenous proteins, or DC-T cell conjugate formation at earlier time points. These observations suggest a paracrine mechanism by which DC-associated HA facilitates some of the late changes in T cell activation. Although T cells constitutively expressed mRNAs for HA synthases and hyaluronidases, their surface HA expression became detectable only after activation. Oligomeric Pep-1 and bovine proteoglycan both inhibited mitogen-triggered T cell activation in the absence of DC, suggesting an autocrine mechanism by which HA expressed by T cells assists their own activation processes. Finally, adoptively transferred DO11.10 T cells showed progressive mitosis when stimulated with Ag-pulsed DC in living animals, and this clonal expansion was inhibited significantly by administration of Pep-1 oligomer. Our findings may introduce a new concept that relatively simple carbohydrate moieties expressed on DC and perhaps T cells play an important immunomodulatory role during Ag presentation.
authors.affiliation: Department of Dermatology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Mummert
authors.forename: Diana
authors.initials: D
authors.lastname: Mummert
authors.forename: Dale
authors.initials: D
authors.lastname: Edelbaum
authors.forename: Francis
authors.initials: F
authors.lastname: Hui
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Matsue
authors.forename: Akira
authors.initials: A
authors.lastname: Takashima
mesh_terms: D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D001667:Binding, Competitive / Q000276:immunology; D002417:Cattle; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology*; D007274:Injections, Intraperitoneal; D008213:Lymphocyte Activation / Q000187:drug effects; D008546:Melanoma, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D011108:Polymers / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000276:immunology; D011509:Proteoglycans / Q000378:metabolism / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D014407:Tumor Cells, Cultured
chemical_list: D000276:Adjuvants, Immunologic; D018984:Epitopes, T-Lymphocyte; D009842:Oligopeptides; D011108:Polymers; D011509:Proteoglycans; D011092:Polyethylene Glycols; D006820:Hyaluronic Acid