title: Acidosis increases MHC class II-restricted presentation of a protein endowed with a pH-dependent heparan sulfate-binding ability.
abstract: Heparan sulfate proteoglycans (HSPGs) are ubiquitously expressed molecules that participate in numerous biological processes. We previously showed that HSPGs expressed on the surface of APCs can serve as receptors for a hybrid protein containing an HS ligand and an Ag, which leads to more efficient stimulation of Th cells. To investigate whether such behavior is shared by proteins with inherent HS-binding ability, we looked for proteins endowed with this characteristic. We found that diphtheria toxin and its nontoxic mutant, called CRM197, can interact with HS. However, we observed that their binding ability is higher at pH 6 than at pH 7.4. Therefore, as extracellular acidosis occurs during infection by various micro-organisms, we assessed whether HS-binding capacity affects MHC class II-restricted presentation at different pHs. We first observed that pH decrease allows CRM197 binding to HSPG-expressing cells, including APCs. Then, we showed that this interaction enhances Ag uptake and presentation to Th cells. Lastly, we observed that pH decrease does not affect processing and presentation abilities of the APCs. Our findings show that acidic pH causes an HSPG-mediated uptake and an enhancement of T cell stimulation of Ags with the inherent ability to bind HSPGs pH-dependently. Furthermore, they suggest that proteins from micro-organisms with this binding characteristic might be supported more efficiently by the adaptive immune system when acidosis is triggered during infection.
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'Etude et de Recherche en Immunoanalyse, 91191 Gif-Sur-Yvette, 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'Etude et de Recherche en Immunoanalyse, 91191 Gif-Sur-Yvette, France;
authors.forename: Alexandra
authors.initials: A
authors.lastname: Savatier
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut de Biologie et Technologies de Saclay, Service d'Ingénierie Moléculaire des Protéines, Laboratoire de Toxinologie Moléculaire et Biotechnologies, 91191 Gif-Sur-Yvette, France;
authors.forename: Grégory
authors.initials: G
authors.lastname: Upert
authors.affiliation: Université Grenoble Alpes, Institut de Biologie Structurale, 38000 Grenoble, France; Centre National de la Recherche Scientifique, Institut de Biologie Structurale, 38000 Grenoble, France; and Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Biologie Structurale, 38000 Grenoble, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Lortat-Jacob
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'Etude et de Recherche en Immunoanalyse, 91191 Gif-Sur-Yvette, France; michel.leonetti@cea.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Léonetti
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000235:genetics / Q000276:immunology*; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D000941:Antigens; D019812:Heparan Sulfate Proteoglycans; D000949:Histocompatibility Antigens Class II