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

John T. Hunzeker, Michael D. Elftman, Jennifer C. Mellinger, Michael F. Princiotta, Robert H. Bonneau, Mary E. Truckenmiller, Christopher C. Norbury

Research output: Contribution to journalArticle

22 Citations (Scopus)

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-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.

Original languageEnglish (US)
Pages (from-to)183-194
Number of pages12
JournalJournal of Immunology
Volume186
Issue number1
DOIs
StatePublished - Jan 1 2011

Fingerprint

Cross-Priming
Dendritic Cells
Glucocorticoids
T-Lymphocytes
Corticosterone
Psychological Stress
Aptitude
Glucocorticoid Receptors
Lymphoid Tissue
Proteasome Endopeptidase Complex
Endocytosis
Cellular Immunity
Proteolysis
Immune System

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Hunzeker, John T. ; Elftman, Michael D. ; Mellinger, Jennifer C. ; Princiotta, Michael F. ; Bonneau, Robert H. ; Truckenmiller, Mary E. ; Norbury, Christopher C. / A marked reduction in priming of cytotoxic CD8+ T cells mediated by stress-induced glucocorticoids involves multiple deficiencies in cross-presentation by dendritic cells. In: Journal of Immunology. 2011 ; Vol. 186, No. 1. pp. 183-194.
@article{59dd4c31ec7747cd9fe3bc3a1f328253,
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-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.",
author = "Hunzeker, {John T.} and Elftman, {Michael D.} and Mellinger, {Jennifer C.} and Princiotta, {Michael F.} and Bonneau, {Robert H.} and Truckenmiller, {Mary E.} and Norbury, {Christopher C.}",
year = "2011",
month = "1",
day = "1",
doi = "10.4049/jimmunol.1001737",
language = "English (US)",
volume = "186",
pages = "183--194",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "1",

}

A marked reduction in priming of cytotoxic CD8+ T cells mediated by stress-induced glucocorticoids involves multiple deficiencies in cross-presentation by dendritic cells. / Hunzeker, John T.; Elftman, Michael D.; Mellinger, Jennifer C.; Princiotta, Michael F.; Bonneau, Robert H.; Truckenmiller, Mary E.; Norbury, Christopher C.

In: Journal of Immunology, Vol. 186, No. 1, 01.01.2011, p. 183-194.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A marked reduction in priming of cytotoxic CD8+ T cells mediated by stress-induced glucocorticoids involves multiple deficiencies in cross-presentation by dendritic cells

AU - Hunzeker, John T.

AU - Elftman, Michael D.

AU - Mellinger, Jennifer C.

AU - Princiotta, Michael F.

AU - Bonneau, Robert H.

AU - Truckenmiller, Mary E.

AU - Norbury, Christopher C.

PY - 2011/1/1

Y1 - 2011/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79251549773&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79251549773&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1001737

DO - 10.4049/jimmunol.1001737

M3 - Article

C2 - 21098225

AN - SCOPUS:79251549773

VL - 186

SP - 183

EP - 194

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 1

ER -