title: Heparan sulfates targeting increases MHC class I- and MHC class II-restricted antigen presentation and CD8(+) T-cell response.
abstract: Heparan sulfates (HS) are carbohydrate moieties of HS proteoglycans (HSPGs). They often represent alternative attachment points for proteins or microorganisms targeting receptors. HSPGs, which are ubiquitously expressed, thereby participate in numerous biological processes. We previously showed that MHC class II-restricted antigen presentation is increased when antigens are coupled to HS ligands, suggesting that HSPGs might contribute to adaptive immune responses. Here, we examined if HSPG targeting influences other aspects of immune responses. We found that coupling of an HS ligand to the antigen increases antigen presentation to CD4(+) and CD8(+) T-cells after antigen targeting to membrane immunoglobulins or to MHC-II molecules. Moreover, this increased stimulating capacity correlates with an enhanced CD8(+) immune response in mice. Last, animals control more effectively the growth of Ova-expressing tumour cells when they are immunized with an Ova construct targeting HSPGs and MHC-II molecules. Our results indicate that ubiquitous molecules can influence both MHC class I- and MHC class II-restricted antigen presentation and behave as co-receptors during T-cell stimulation. Moreover, they suggest that tumour-antigens endowed with the ability to target both HSPGs and MHC-II molecules could be of value to increase CD8(+) immune response and control tumour-growth, opening new perspectives for the design of highly immunogenic protein-based vaccines.
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut de Biologie et Technologies de Saclay, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etudes et de Recherches en Immunoanalyse, Gif-Sur-Yvette F-91191, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Knittel
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut de Biologie et Technologies de Saclay, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etudes et de Recherches en Immunoanalyse, Gif-Sur-Yvette F-91191, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Gadzinski
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut de Biologie et Technologies de Saclay, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etudes et de Recherches en Immunoanalyse, Gif-Sur-Yvette F-91191, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Hua
authors.affiliation: Institut Curie, Centre de Recherche, Paris 75005, France; INSERM, U932, Paris F-75005, France; Centre d'Investigation Clinique Biothérapie CICBT 507, Institut Curie, Paris F-75005, France.
authors.forename: Jordan
authors.initials: J
authors.lastname: Denizeau
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut de Biologie et Technologies de Saclay, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etudes et de Recherches en Immunoanalyse, Gif-Sur-Yvette F-91191, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Savatier
authors.affiliation: Institut Curie, Centre de Recherche, Paris 75005, France; INSERM, U932, Paris F-75005, France; Centre d'Investigation Clinique Biothérapie CICBT 507, Institut Curie, Paris F-75005, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: de la Rochère
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut de Biologie et Technologies de Saclay, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etudes et de Recherches en Immunoanalyse, Gif-Sur-Yvette F-91191, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Boulain
authors.affiliation: Institut Curie, Centre de Recherche, Paris 75005, France; INSERM, U932, Paris F-75005, France; Centre d'Investigation Clinique Biothérapie CICBT 507, Institut Curie, Paris F-75005, France.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Amigorena
authors.affiliation: Institut Curie, Centre de Recherche, Paris 75005, France; INSERM, U932, Paris F-75005, France; Centre d'Investigation Clinique Biothérapie CICBT 507, Institut Curie, Paris F-75005, France.
authors.forename: Eliane
authors.initials: E
authors.lastname: Piaggio
authors.affiliation: Institut Curie, Centre de Recherche, Paris 75005, France; INSERM, U932, Paris F-75005, France; Centre d'Investigation Clinique Biothérapie CICBT 507, Institut Curie, Paris F-75005, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Sedlik
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut de Biologie et Technologies de Saclay, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etudes et de Recherches en Immunoanalyse, Gif-Sur-Yvette F-91191, France. Electronic address: michel.leonetti@cea.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Léonetti
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology; D019812:Heparan Sulfate Proteoglycans / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000276:immunology
chemical_list: D019812:Heparan Sulfate Proteoglycans; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D011993:Recombinant Fusion Proteins
keywords: Antigen targeting; Cross presentation; Heparan sulfate; Tumour control