title: Corticosterone impairs MHC class I antigen presentation by dendritic cells via reduction of peptide generation.
abstract: The presentation of viral peptide-MHC class I complexes by antigen presenting cells, such as dendritic cells (DCs), is obligatory for the generation of antiviral effector and memory CD8(+) cytotoxic T lymphocyte (CTL) responses. Prolonged psychological stress is immunosuppressive and undermines primary and memory CTL-mediated antiviral immunity; however, the mechanisms involved are unknown. Using a panel of novel reagents and techniques, we quantitatively measured the effect of the stress-induced hormone corticosterone (CORT) on the efficiency of DCs to process and present virally expressed antigen, characterized the conditions for this CORT-mediated effect, and delineated the components of the MHC class I pathway that were affected. We found that physiologically relevant levels of CORT, prior to infection and acting via the glucocorticoid receptor, suppressed the formation of peptide-MHC class I complexes on the surface of infected DCs. We further showed that this suppression of peptide-MHC class I complexes is via the action of CORT on elements of the class I pathway upstream from TAP that are involved in the generation of antigenic peptides. This CORT-mediated suppression of peptide-class I complexes on DCs also resulted in a marked reduction of their ability to activate a specific T cell hybridoma. These findings offer a mechanism contributing to the stress-induced suppression of host defenses against viral diseases and have implications for the efficacy of antiviral vaccines. At the most fundamental cellular level, this impairment of antigen processing has implications for the regulation of protein degradation in all cells, which is critical to many aspects of immune function.
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA 17033, USA. met11@psu.edu
authors.forename: Mary E
authors.initials: ME
authors.lastname: Truckenmiller
authors.forename: Michael F
authors.initials: MF
authors.lastname: Princiotta
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Norbury
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bonneau
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects* / Q000276:immunology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003345:Corticosterone / Q000494:pharmacology* / Q000502:physiology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D004306:Dose-Response Relationship, Immunologic; D004527:Egg Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000378:metabolism; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D006183:H-2 Antigens / Q000096:biosynthesis / Q000276:immunology* / Q000502:physiology; D006825:Hybridomas; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D010047:Ovalbumin / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D010452:Peptide Biosynthesis / Q000187:drug effects* / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000276:immunology; D011965:Receptors, Glucocorticoid / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014616:Vaccinia virus / Q000276:immunology
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D004527:Egg Proteins; D000939:Epitopes; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D007166:Immunosuppressive Agents; C110366:OVA-8; D010446:Peptide Fragments; D011965:Receptors, Glucocorticoid; C486171:Tap1 protein, mouse; C489516:Tap2 protein, mouse; D010047:Ovalbumin; D003345:Corticosterone