A Marked Reduction in Priming of Cytotoxic CD8+ T Cells Mediated by Stress-Induced Glucocorticoids Involves Multiple Deficiencies in Cross-Presentation by Dendritic Cells
| Autor: | Michael D. Elftman, Jennifer C. Mellinger, M.E. Truckenmiller, John Hunzeker, Christopher C. Norbury, Michael F. Princiotta, Robert H. Bonneau |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Cytotoxicity
Immunologic Male Ovalbumin T cell Immunology Priming (immunology) chemical and pharmacologic phenomena Mice Transgenic Biology Lymphocyte Activation Article Immobilization Mice Immune system Cross-Priming MHC class I medicine Immunology and Allergy Cytotoxic T cell Animals Cells Cultured Immunosuppression Therapy Mice Knockout Cross-presentation Dendritic Cells Coculture Techniques Mice Inbred C57BL CTL medicine.anatomical_structure biology.protein Corticosterone CD8 Stress Psychological T-Lymphocytes Cytotoxic |
| Popis: | 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-OVA257–264-specific T cells. Using a murine model of psychological stress and OVA-loaded β2-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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|