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A marked reduction in priming of cytotoxic CD8+ T cells mediated by stress-induced glucocorticoids involves multiple deficiencies in cross-presentation by dendritic cells.

TitleA marked reduction in priming of cytotoxic CD8+ T cells mediated by stress-induced glucocorticoids involves multiple deficiencies in cross-presentation by dendritic cells.
Publication TypeJournal Article
Year of Publication2011
AuthorsHunzeker JT, Elftman MD, Mellinger JC, Princiotta MF, Bonneau RH, Truckenmiller ME, Norbury CC
JournalJ Immunol
Volume186
Issue1
Pagination183-94
Date Published2011 Jan 1
ISSN1550-6606
KeywordsAnimals, Cells, Cultured, Coculture Techniques, Corticosterone, Cross-Priming, Cytotoxicity, Immunologic, Dendritic Cells, Immobilization, Immunosuppression, Lymphocyte Activation, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Ovalbumin, Stress, Psychological, T-Lymphocytes, Cytotoxic
Abstract

<p>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.</p>

DOI10.4049/jimmunol.1001737
Alternate JournalJ. Immunol.
Citation KeyCK102
PubMed ID21098225
PubMed Central IDPMC3701459
Grant List2 T32 CA60395 / CA / NCI NIH HHS / United States
AI056094 / AI / NIAID NIH HHS / United States
AI065702 / AI / NIAID NIH HHS / United States
AI070537 / AI / NIAID NIH HHS / United States
C06 RR-15428 / RR / NCRR NIH HHS / United States
R01 AI056094 / AI / NIAID NIH HHS / United States