Abstract
Hyaluronan (HA), a large glycosaminoglycan composed of d-N-acetylglucosamine and d-glucuronic acid, is expressed in virtually all tissues and has long been considered to serve as a structural component or filling material in the tissue interstitium (Filler Theory). This idea was revised with the discovery of HA-binding proteins that introduced the concept that HA may also serve as an adhesive substrate for cellular trafficking (Adhesion Theory). Most recently, it has been shown that HA fragments can deliver maturational signals to dendritic cells (DCs) and high molecular weight HA polymers can deliver costimulatory signals to T-cells (Signaling Theory). Thus, HA may represent an important component of the immune system. Recently, we have evaluated the impact of HA on Langerhans cell (LC) maturation and migration using a novel peptide inhibitor of HA function, termedPep-1 (GAHWQFNALTVR). As skin-specific members of the DC family, LCs are crucial for the initiation of cutaneous immune responses. Local injections of Pep1 prevented hapten-induced LC migration from, the epidermis, providing the first experimental evidence that HA facilitates their emigration. Moreover, Pep-1 also significantly inhibited the hapteninduced maturation of LCs in vivo as assessed by cell morphology, costimulatory molecule expression, and their ability to induce proliferation of allogeneic T-cells. HA therefore has dual functionality to facilitate LC migration and maturation, the two critical events for the initiation of adaptive immune responses. Finally, we have observed that DC-dependent, antigen-specific T-cell proliferation and cytokine secretion is blocked by Pep-1. These results have revealed a previously unrecognized role for HA in antigen presentation. Thus, far from an inert structural biopolymer, HA represents a multifunctional carbohydrate mediator of immune processes.
Similar content being viewed by others
References
Streilein JW, Toews GT, Gilliam JN, Bergstresser PR: Tolerance or hypersensitivity to 2,4-dinitro-1-fluorobenzene: the role of Langerhans cell density within epidermis. J Invest Dermatol 1980;74:319–322.
Streilein JW, Bergstresser PR: Langerhans cell function dictates induction of contact hypersen sitivity or unresponsiveness to DNFB in Syrian hamsters. J Invest Dermatol 1981;77:272–277.
Pehamberger H, Stingl LA, Pogantsch S, Steiner G, Wolff K, Stingl G: Epidermal cell-induced generation of cytotoxic T-lymphocyte responses against alloantigens or TNP-modified syngeneic cells: requirement for Ia-positive Langerhans cells. J Invest Dermatol 1983;81:208–211.
Hauser C, Yokoyama WM, Katz SI: Characterization of primary T helper cell activation and T helper cell lines stimulated by hapten-modified, cultured Langerhans cells. J Invest Dermatol 1989;93:649–655.
Kolde G: Effects of immunological responsiveness on Langerhans cell behavior in contact sensitization. Exp Dermatol 1994;3:269–275.
Antonopoulos C, Cumberbatch M, Dearman RJ, Daniel RJ, Kimber I, Groves RW: Functional caspase-1 is required for Langerhans cell migration and optimal contact sensitization in mice. J Immunol 2001;166: 3672–3677.
Wang B, Amerio P, Sauder DN: Role of cytokines in epidermal Langerhans cell migration. J Leukoc Biol 1999;66:33–39.
Cumberbatch M, Dearman RJ, Griffiths CE Kimber I: Langerhans cell migration. Clin Exp Dermatol 2000; 25:413–418.
Kimber I, Cumberbatch M, Dearman RJ, Bhushan M, Griffiths CE: Cytokines and chemokines in the initiation and regulation of epidermal Langerhans cell mobilization. Br J Dermatol 2000;142:401–412.
Fraser JR, Laurent TC, Laurent UB: Hyaluronan: its nature, distribution, functions and turnover. J Intern Med 1997;242:27–33.
Tamaki K, Yasaka N, Chang CH, et al.: Identification and characterization of novel dermal Thy-1 antigen-bearing dendritic cells in murine skin. J Invest Dermatol 1996;106:571–575.
Termeer CC, Hennies J, Voith U, et al.: Oligosaccharides of hyaluronan are potent activators of dendritic cells. J Immunol 2000;165:1863–1870.
Galandrini R, Galluzzo E, Albi N, Grossi CE, Velardi A: Hyaluronate is constimulatory for human T cell effector functions and binds to CD44 on activated T cells. J Immunol 1994;153:21–31.
Dirks W, Schöne S, Uphoff C, Quentmeier H, Pradella S, Drexler HG: Expression and function of CD95 (FAS/APO-1) in leukemia-lymphoma tumour lines. Br J Haematol 1997;96:584–593.
Banchereau J, Briere F, Caux C, et al: Immunobiology of dendritic cells. Annu Rev Immunol 2000;18: 767–811.
Tamaki K, Fujiwara H, Katz SI: The role of epidermal cells in the induction and suppression of contact sensitivity. J Invest Dermatol 1981;76:275–278.
Sullivan S, Bergstresser PR, Tigelaar RE, Streilein JW: Induction and regulation of contact hypersensitivity by resident, bone-marrow derived, dendritic epidermal cells: Langerhans cells and Thy-1+epidermal cells. J Immunol 1986;137:2460–2467.
Moll H, Fuchs H, Blank C, Rollinghoff M: Langerhans cells transport Leishmania major from the infected skin to the draining lymph node for presentation to antigenspecific T cells. Eur J Immunol 1993;23:1595–1601.
Moll H, Flohé S, Röllinghoff M: Dendritic cells in Leishmania major-immune mice harbor persistent parasites and mediate an antigen-specific T cell immune response. Eur J Immunol 1995;25:693–699.
Nonacs R, Humborg C, Tam JP, Steinman RM: Mechanisms of mouse spleen dendritic cell function in the generation of influenza-specific, cytolytic T lymphocytes. J Exp Med 1992;176:519–529.
Inaba K, Inaba M, Naito M, Steinman RM: Dendritic cell progenitors phagocytose particulates, including bacillus Calmette-Guerin organisma, and sensitize mice to mycobacterial antigens in vivo. J Exp Med 1993;178:479–488.
Grabbe S, Bruvers S, Gallo RL, Knisely TL, Nazareno R, Granstein RD: Tumor antigen presentation by murine epidermal cells. J Immunol 1991;146:3656–3661.
Ludewig B, Odermatt B, Landmann S, Hengartner H, Zinkernagel RM: Dendritic cells induce autoimmune diabetes and maintain disease via De Novo formation of local lymphoid tissue. J Exp Med 1998;188:1493–1501.
Maurer D, Stingl G: Dendritic cells in the context of skin immunity; in Lotze MT, Thomson AW (eds): Dendritic Cells: Biology and Clinical Applications. San Diego, Academic, 1999, pp 111–122.
Cumberbatch M, Kimber I: Tumour necrosis factor-α is required for accumulation of dendritic cells in draining lymph nodes and for optimal contact sensitization. Immunology 1995;84:31–35.
Roake JA, Rao AS, Morris PJ, Larsen CP, Hankins DF, Austyn JM: Dendritic cell loss from nonlymphoid tissues after systemic administration of lipopolysaccharide, tumor necrosis factor, and interleukin 1. J Exp Med 1995;181:2237–2247.
Dieu M-C, Vanbervliet B, Vicari A, et al: Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sties. J Exp Med 1998;188:373–386.
Sozzani S, Allavena P, D'Amico G, et al: Differential regulation of chemokine receptors during dendritic cell maturation: a model for their trafficking properties. J Immunol 1998;161:1083–1086.
Ogata M, Zhang Y, Wang Y, et al: Chemotactic response toward chemokines and its regulation by transforming growth factor-β1 of murine bone marrow hematopoietic progenitor cell-derived different subset of dendritic cells. Blood 1999;93:3225–3232.
Saeki H, Moore AM, Brown MJ, Hwang ST: Secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes. J Immunol 1999;162:2472–2475.
Liu YJ, Kanzler H, Soumelis V, Gilliet M: Dendritic cell lineage, plasticity and cross-regulation. Nat Immunol 2001;2:585–589.
Giannoukakis N, Bonham CA, Qian S, et al: Prolongation of cardiac allograft survival using dendritic cells treated with NF- ⦊B decoy oligodeoxyribonucleotides. Mol Ther 2000;1:430–437.
Morelli AE, Larregina AT, Ganster RW, et al: Recombinant adenovirus induces maturation of dendritic cells via an NF- ⦊B-dependent pathway. J Virol 2000; 74:9617–9628.
Weigel PH, Hascall VC, Tammi M: Hyaluronan synthases. J Biol Chem 1997;272:13,997–14,000.
Mohamadzadeh M, DeGrendele H, Arizpe H, Estess P, Siegelman M: Proinflammatory stimuli regulate endothelial hyaluronan expression and CD44/HA-dependent primary adhesion. J Clin Invest 1998;101:97–108.
Estess P, Nandi A, Mohamadzadeh M, Siegelman MH: Interleukin 15 induces endothelial hyaluronan expression in vitro and promotes activated T cell extravasation through a CD44-dependent pathway in vivo. J Exp Med 1999;190:9–19.
Camenisch TD, Spicer AP, Brehm-Gibson T, et al: Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. J Clin Invest 2000;106:349–360.
Frost GI, Csoka TB, Wong T, Stern R: Purification, cloning, and expression of human plasma hyaluronidase. Biochem Biophys Res Commun 1997; 236:10–15.
Gmachl M, Sagan S, Ketter S, Kreil G: The human sperm protein PH-20 has hyaluronidase activity. FEBS Lett 1993;336:545–548.
Lepperdinger G, Strobl B, Kreil G: HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity. J Biol Chem 1998;273:22,466–22,470.
Csoka TB, Frost GI, Wong T, Stern R: Purification and microsequencing of hyaluronidase isozymes from human urine. FEBS Lett 1997;417:307–410.
Roden L, Campbell P, Fraser JR, Laurent TC, Pertoft H, Thompson JN: Enzymic pathways of hyaluronan catabolism. Ciba Found Symp 1989;143:60–76.
Natowicz MR, Short MP, Wang Y, et al.: Clinical and biochemical manifestations of hyaluronidase deficiency. N Engl J Med 1996;335:1029–1033.
Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B: CD44 is the principal cell surface receptor for hyaluronate. Cell 1990;61:1303–1313.
Miyake K, Underhill CB, Lesley J, Kincade PW: Hyaluronate can function as a cell adhesion molecule and CD44 participates in hyaluronate recognition. J Exp Med 1990;172:69–75.
Hardingham TE: The role of link-protein in the structure of cartilage proteoglycan aggregates. Biochem J 1979;177:237–247.
Watanabe H, Cheung SC, Itano N, Kimata K, Yamada Y: Identification of hyaluronan-binding domains of aggrecan. J Biol Chem 1997;272:28,057–28,065.
LeBaron RG, Zimmermann DR, Ruoslahti E: Hyaluronate binding properties of versican. J Biol Chem 1992;267:10,003–10,010.
Delpech B, Halavent C: Characterization and purification from human brain of a hyaluronic acid-binding glycoprotein, hyaluronectin. J Neurochem 1981;36:855–859.
Rauch U, Karthikeyan L, Maurel P, Margolis RU, Margolis RK: Cloning and primary structure of neurocan, a developmentally regulated, aggregating chondroitin sulfate proteoglycan of brain. J Biol Chem 1992;267:19,536–19,547.
Banerji S, Ni J, Wang SX, et al.: LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 1999;144:789–801.
Prevo R, Banerji S, Ferguson DJ, Clasper S, Jackson DG: Mouse LYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium. J Biol Chem 2001;276:19,420–19,430.
Entwistle J, Hall CL, Turley EA: HA receptors: regulators of signalling to the cytoskeleton. J Cell Biochem 1996;61:569–577.
Siegelman MH, DeGrendele HC, Estess P: Activation and interaction of CD44 and hyaluronan in immunological systems. J Leukoc Biol 1999;66:315–321.
Johnson P, Maiti A, Brown KL, Li R: A role for the cell adhesion molecule CD44 and sulfation in leukocyte-endothelial cell adhesion during an inflammatory response? Biochem Pharmacol 2000;59:455–465.
Toyama-Sorimachi N, Miyake K, Miyasaka M: Activation of CD44 induces ICAM-1/LFA-1-independent, Ca2+ Mg2+-independent adhesion pathway in lymphocyte-endothelial cell interaction. Eur J Immunol 1993;23:439–446.
Fujii K, Tanaka Y, Hubscher S, Saito K, Ota T, Eto S: Cross-linking of CD44 on rheumatoid synovial cells upregulates VCAM-1. J Immunol 1999;162:2391–2398.
Guo YJ, Ma J, Wong JH, et al.: Monoclonal anti-CD44 antibody acts in synergy with anti-CD2 but inhibits anti-CD3 or T cell receptor-mediated signaling in murine T cell hybridomas. Cell Immunol 1993; 152:186–199.
Bourguignon LY, Lokeshwar VB, Chen X, Kerrick WG: Hyaluronic acid-induced lymphocyte signal transduction and HA receptor (GP85/CD44)-cytoskeleton interaction. J Immunol 1993;151: 6634–6644.
Khaldoyanidi S, Moll J, Karakhanova S, Herrlich P, Ponta H: Hyaluronate-enhanced hematopoiesis: two different receptors trigger the release of interleukin-β and interleukin-6 from bone marrow macrophages. Blood 1999;94:940–949.
Horton MR, Burdick MD, Strieter RM, Bao C, Noble PW: Regulation of hyaluronan-induced chemokine gene expression by IL-10 and IFN-γ in mouse macrophages. J Immunol 1998;160:3023–3030.
Fitzgerald KA, O'Neill LA: Characterization of CD44 induction by IL-1: a critical role for Egr-1. J Immunol 1999;162:4920–4927.
McKallip RJ, Do Y, Fisher MT, Robertson JL, Nagarkatti PS, Nagarkatti M: Role of CD44 in activation-induced enhanced T cell response to conventional and superantigens. Int Immunol 2002;14:1015–1026.
Takahashi K, Eto H, Tanabe KK: Involvement of CD44 in matrix metalloproteinase-2 regulation in human melanoma cells. Int J Cancer 1999;80:387–395.
Yu Q, Stamenkovic I: Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev 1998;13:35–48.
Knutson JR, Iida J, Fields GB, McCarthy JB: CD44/chondroitin sulfate proteoglycan and α2β1 integrin mediate human melanoma cell migration on type IV collagen and invasion of basement membranes. Mol Biol Cell 1996; 7: 383–396.
Jalkanen S, Jalkanen M: Lymphocyte CD44 binds the COOH-terminal heparin-binding domain of fibronectin. J Cell Biol 1992;116:817–825.
Sleeman JP, Kondo K, Moll J, Ponta H, Herrlich P: Variant exons v6 and v7 together expand the repertoire of glycosaminoglycans bound by CD44. J Biol Chem 1997;272:31,837–31,844
Weber GF, Ashkar S, Glimcher MJ, Cantor H: Receptor-ligand interaction between CD44 and osteopontin (Eta-1). Science 1996;271:509–512.
Mummert ME, Mohamadzadeh M, Mummert DI, Mizumoto N, Takashima A: Development of a peptide inhibitor of hyaluronan-mediated leukocyte trafficking. J Exp Med 2000;192:769–779.
Bárdos T, Kamath RV, Mikecz K, Glant TT: Antiinflammatory and chondroprotective effect of TSG-6 (tumor necrosis factor-α-stimulated gene-6) in murine models of experimental arthritis. Am J Pathol 2001;159:1711–1721.
Gerdin B, Hallgren R: Dynamic role of hyaluronan (HYA) in connective tissue activation and inflammation. J Intern Med 1997;242:49–55.
Ogawa M, Hirano H, Tsubaki H, Kodama H, Tanaka T: The role of cytokines in cervical ripening: correlations between the concentrations of cytokines and hyaluronic acid in cervical mucus and the induction of hyaluronic acid production by inflammatory cytokines by human cervical fibroblasts. Am J Obstet Gynecol 1998; 179:105–110.
Tammi R, Ripellino JA, Margolis RU, Maibach HI, Tammi M: Hyaluronate accumulation in human epidermis treated with retinoic acid in skin organ culture. J Invest Dermatol 1989;92:326–332.
Agren UM, Tammi M, Tammi R: Hydrocortisone regulation of hyaluronan metabolism in human skin organ culture. J Cell Physiol 1995;164:240–248.
Pienimaki JP, Rilla K, Fulop C, et al.: Epidermal growth factor activates hyaluronan synthase 2 in epidermal keratinocytes and increases pericellular and intracellular hyaluronan. J Biol Chem 2001;276:20,428–20,435.
Hayen W, Goebeler M, Kumar S, Riessen R, Nehls V: Hyaluronan stimulates tumor cell migration by modulating the fibrin fiber architecture. J Cell Sci 1999;112(Pt 13):2241–2251.
Brecht M, Mayer U, Schlosser E, Prehm P: Increased hyaluronate synthesis is required for fibroblast detachment and mitosis. Biochem J 1986;239:445–450.
Evanko SP, Angello JC, Wight TN: Formation of hyaluronan- and versican-rich pericellular matrix is required for proliferation and migration of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1999;19:1004–1013.
Hardwick C, Hoare K, Owens R, et al.: Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility. J Cell Biol 1992;117:1343–1350.
DeGrendele H, Estess P, Picker LJ, Siegelman MH: CD44 and its ligand hayluronate mediate rolling under physiologic flow: a novel lymphocyte-endothelial cell primary adhesion pathway. J Exp Med 1996;183: 1119–1130.
DeGrendele HC, Estess P, Siegelman MH: Requirement for CD44 in activated T cell extravasation into an inflammatory site. Science 1997;278:672–675.
Protin U, Schweighoffer T, Jochum W, Hilberg F: CD44-deficient mice develop normally with changes in subpopulations and recirculation of lymphocyte subsets. J Immunol 1999;163:4917–4923.
Tang A, Amagai M, Granger LG, Stanley JR, Udey MC: Adhesion of epidermal Langerhans cells to keratinocytes mediated by E-cadherin. Nature 1993;361: 82–85.
Price AA, Cumberbatch M, Kimber I, Ager A: α6 integrins are required for Langerhans cell migration from the epidermis. J Exp Med 1997;186:1725–1735.
Osada A, Nakashima H, Furue M, Tamaki K: Up regulation of CD44 expression by tumor necrosis factor-α is neutralized by interleukin-10 in Langerhans cells. J Invest Dermatol 1995;105:124–127.
Weiss JM, Sleeman J, Renkl AC, et al: An essential role for CD44 variant isoforms in epidermal Langerhans cell and blood dendritic cell function. J Cell Biol 1997;137:1137–1147.
Weiss JM, Renkl AC, Maier CS, et al: Osteopontin is involved in the initiation of cutaneous contact hypersensitivity by inducing Langerhans and dendritic cell migration to lymph nodes. J Exp Med 2001;194: 1219–1229.
Xu S, Ariizumi K, Caceres-Dittmar G, Edelbaum D, Bergstresser PR, Takashima A: Successive generation of antigen-presenting, dendritic cell lines from murine epidermis. J Immunol 1995;154:2697–2705.
Matsue H, Matsue K, Walters M, Okumura K, Yagita H, Takashima A: Induction of antigen-specific immunosuppression by CD95L cDNA-transfected “killer” dendritic cells. Nat Med 1999;5:930–937.
Price EA, Coombe DR, Murray JC: Endothelial CD44H mediates adhesion of a melanoma cell line to quiescent human endothelial cells in vitro. Int J Cancer 1996;65:513–518.
Föger N, Marhaba R, Zöller M: CD44 supports T cell proliferation and apoptosis by apposition of protein kinases. Eur J Immunol 2000;30:2888–2899.
Mummert ME, Mummert D, Edelbaum D, Hui F, Matsue H, Takashima A: Synthesis and surface expression of hyaluronan by dendritic cells and its potential role in antigen presentation. J Immunol 2002;169: 4322–4331.
Do Y, Nagarkatti PS, Nagarkatti, M: Role of CD44 and hyaluronic acid (HA) in activation of alloreactive and antigen-specific T cells by bone marrow-derived dendritic cells. J Immunother 2004;27:1–12.
Hodge-Dufour J, Noble PW, Horton MR, et al: Induction of IL-12 and chemokines by hyaluronan requires adhesion-dependent priming of resident but not elicited macrophages. J Immunol 1997;159: 2492–2500.
McKee CM, Penno MB, Cowman M, et al: Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages: the role of HA size and CD44. J Clin Invest 1996;98:2403–2413.
Horton MR, McKee CM, Bao C, et al: Hyaluronan fragments synergize with interferon-γ to induce the C-X-C chemokines mig and interferon-inducible protein-10 in mouse macrophages. J Biol Chem 1998;273: 35,088–35,094.
Termeer C, Benedix F, Sleeman J, et al: Oligosaccharides of hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med 2002;195:99–111.
Taylor KR, Trowbridge JM, Rudisill JA, Termeer CC, Simon JC, Gallo RL: Hyaluronan fragments stimulate dermal endothelial recognition of injury through TLR4. J Biol Chem 2004;279:17079–17084.
Teder P, Vandivier RW, Jiang D, et al: Resolution of lung inflammation by CD44. Science 2002;296: 155–158.
Suzuki H, Wang B, Shivji GM, et al: Imiquimod, a topical immune response modifier, induces migration of Langerhans cells. J Invest Dermatol 2000;114: 135–141.
Rattis FM, Peguet-Navarro J, Staquet MJ, et al: Expression and function of B7-1 (CD80) and B7-2 (CD86) on human epidermal Langerhans cells. Eur J Immunol 1996;26:449–453.
Nuriya S, Yagita H, Okumura K, Azuma M: The differential role of CD86 and CD80 co-stimulatory molecules in the induction and the effector phases of contact hypersensitivity. Int Immunol 1996;8:917–926.
Mummert DI, Takashima A, Ellinger L, Mummert ME: Involvement of hyaluronan in epidermal Langerhans cell maturation and migration in vivo. J Dermatol Sci 2003;33:91–97.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mummert, M.E. Immunologic roles of hyaluronan. Immunol Res 31, 189–205 (2005). https://doi.org/10.1385/IR:31:3:189
Issue Date:
DOI: https://doi.org/10.1385/IR:31:3:189