title: Enhanced and prolonged cross-presentation following endosomal escape of exogenous antigens encapsulated in biodegradable nanoparticles.
abstract: CD8(+) T-cell responses are critical in the immunological control of tumours and infectious diseases. To prime CD8(+) T cells against these cell-associated antigens, exogenous antigens must be cross-presented by professional antigen-presenting cells (APCs). While cross-presentation of soluble antigens by dendritic cells is detectable in vivo, the efficiency is low, limiting the clinical utility of protein-based vaccinations. To enhance the efficiency of presentation, we generated nanoparticles from a biodegradable polymer, poly(D,L-lactide-co-glycolide) (PLGA), to deliver antigen into the major histocompatibility complex (MHC) class I antigen presentation pathway. In primary mouse bone marrow-derived dendritic cells (BMDCs), the MHC class I presentation of PLGA-encapsulated ovalbumin (OVA) stimulated T cell interleukin-2 secretion at 1000-fold lower concentration than soluble antigen and 10-fold lower than antigen-coated latex beads. The microparticles also served as an intracellular antigen reservoir, leading to sustained MHC class I presentation of OVA for 72 hr, decreasing by only 20% after 96 hr, a time at which the presentation of soluble and latex bead-associated antigens was undetectable. Cytosol extraction demonstrated that antigen delivery via PLGA particles increased the amount of protein that escaped from endosomes into the cytoplasm, thereby increasing the access of exogenous antigen to the classic MHC class I loading pathway. These data indicate that the unique properties of PLGA particle-mediated antigen delivery dramatically enhance and sustain exogenous antigen presentation by MHC class I, potentially facilitating the clinical use of these particles in vaccination.
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.forename: Anne L
authors.initials: AL
authors.lastname: Ackerman
authors.forename: Virginia
authors.initials: V
authors.lastname: Cody
authors.forename: Alessandra
authors.initials: A
authors.lastname: Giodini
authors.forename: Ella R
authors.initials: ER
authors.lastname: Hinson
authors.forename: Peter
authors.initials: P
authors.lastname: Cresswell
authors.forename: Richard L
authors.initials: RL
authors.lastname: Edelson
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hanlon
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D001672:Biocompatible Materials; D001673:Biodegradation, Environmental; D002460:Cell Line; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D011992:Endosomes / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D019344:Lactic Acid; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D049329:Nanostructures; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D001672:Biocompatible Materials; D000949:Histocompatibility Antigens Class II; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D012710:Serum Albumin, Bovine; D019344:Lactic Acid; D010047:Ovalbumin