title: A marked reduction in priming of cytotoxic CD8+ T cells mediated by stress-induced glucocorticoids involves multiple deficiencies in cross-presentation by dendritic cells.
abstract: Protracted psychological stress elevates circulating glucocorticoids, which can suppress CD8(+) T cell-mediated immunity, but the mechanisms are incompletely understood. Dendritic cells (DCs), required for initiating CTL responses, are vulnerable to stress/corticosterone, which can contribute to diminished CTL responses. Cross-priming of CD8(+) T cells by DCs is required for initiating CTL responses against many intracellular pathogens that do not infect DCs. We examined the effects of stress/corticosterone on MHC class I (MHC I) cross-presentation and priming and show that stress/corticosterone-exposed DCs have a reduced ability to cross-present OVA and activate MHC I-OVA(257-264)-specific T cells. Using a murine model of psychological stress and OVA-loaded β(2)-microglobulin knockout "donor" cells that cannot present Ag, DCs from stressed mice induced markedly less Ag-specific CTL proliferation in a glucocorticoid receptor-dependent manner, and endogenous in vivo T cell cytolytic activity generated by cross-presented Ag was greatly diminished. These deficits in cross-presentation/priming were not due to altered Ag donation, Ag uptake (phagocytosis, receptor-mediated endocytosis, or fluid-phase uptake), or costimulatory molecule expression by DCs. However, proteasome activity in corticosterone-treated DCs or splenic DCs from stressed mice was partially suppressed, which limits formation of antigenic peptide-MHC I complexes. In addition, the lymphoid tissue-resident CD11b(-)CD24(+)CD8α(+) DC subset, which carries out cross-presentation/priming, was preferentially depleted in stressed mice. At the same time, CD11b(-)CD24(+)CD8α(-) DC precursors were increased, suggesting a block in development of CD8α(+) DCs. Therefore, glucocorticoid-induced changes in both the cellular composition of the immune system and intracellular protein degradation contribute to impaired CTL priming in stressed mice.
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Hunzeker
authors.forename: Michael D
authors.initials: MD
authors.lastname: Elftman
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Mellinger
authors.forename: Michael F
authors.initials: MF
authors.lastname: Princiotta
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bonneau
authors.forename: Mary E
authors.initials: ME
authors.lastname: Truckenmiller
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Norbury
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D003345:Corticosterone / Q000096:biosynthesis / Q000502:physiology*; D045142:Cross-Priming / Q000187:drug effects / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects* / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D007103:Immobilization; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology / Q000378:metabolism; D013315:Stress, Psychological / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D010047:Ovalbumin; D003345:Corticosterone