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CpG-matured murine plasmacytoid dendritic cells are capable of in vivo priming of functional CD8 T cell responses to endogenous but not exogenous antigens.

Salio M, Palmowski MJ, Atzberger A, Hermans IF, Cerundolo V - J. Exp. Med. (2004)

Bottom Line: In vitro experiments have shown that upon maturation, human and murine PDCs develop into potent immunostimulatory cells; however, their ability to prime an immune response in vivo remains to be addressed.In contrast, immature PDCs are unable to prime antigen-specific CTLs.Our results underline the heterogeneity and plasticity of different antigen-presenting cells, and reveal an important role of mature PDCs in priming CD8 responses to endogenous antigens, in addition to their previously reported ability to modulate antiviral responses via type I IFN.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research Tumor Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headley Way, OX3 9DS Oxford, UK. mariolina.salio@imm.ox.ac.uk

ABSTRACT
Plasmacytoid dendritic cells (PDCs) are a unique leukocyte population capable of secreting high levels of type I interferon (IFN) in response to viruses and bacterial stimuli. In vitro experiments have shown that upon maturation, human and murine PDCs develop into potent immunostimulatory cells; however, their ability to prime an immune response in vivo remains to be addressed. We report that CpG-matured murine PDCs are capable of eliciting in naive mice antigen-specific CTLs against endogenous antigens as well as exogenous peptides, but not against an exogenous antigen. Type I IFN is not required for priming, as injection of CpG-matured PDCs into type I IFN receptor-deficient mice elicits functional CTL responses. Mature PDCs prime CTLs that secrete IFN-gamma and protect mice from a tumor challenge. In contrast, immature PDCs are unable to prime antigen-specific CTLs. However, mice injected with immature PDCs are fully responsive to secondary antigenic challenges, suggesting that PDCs have not induced long-lasting tolerance via anergic or regulatory T cells. Our results underline the heterogeneity and plasticity of different antigen-presenting cells, and reveal an important role of mature PDCs in priming CD8 responses to endogenous antigens, in addition to their previously reported ability to modulate antiviral responses via type I IFN.

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Intravenous injection of CpG-matured male PDCs induces CTL responses. (A) C57BL/6 mice (n = 5) were injected i.v. with 105 male MDC or PDCs, immature or CpG matured. Control animals were injected with female MDC. CTL responses were assessed in the blood by ex vivo FACS® analysis using UTY246–254-H-2-Db tetramers 7 d after priming. Mean proportions of tetramer+ cells as a percentage of CD8 cells (± SEM) for each group are shown. (B) C57BL/6 mice (n = 5) were injected with graded numbers of male CpG-matured MDC (gray bars) or PDCs (black bars) and boosted after 1 wk with UV-inactivated vaccinia-UTY246–254 minigene. CTL responses were assessed in the blood by ex vivo tetramer staining 8 d after boosting. Tetramer stainings of control mice, primed by female MDC or by vaccinia-UTY246–254 minigene alone, are shown (white bars).
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fig1: Intravenous injection of CpG-matured male PDCs induces CTL responses. (A) C57BL/6 mice (n = 5) were injected i.v. with 105 male MDC or PDCs, immature or CpG matured. Control animals were injected with female MDC. CTL responses were assessed in the blood by ex vivo FACS® analysis using UTY246–254-H-2-Db tetramers 7 d after priming. Mean proportions of tetramer+ cells as a percentage of CD8 cells (± SEM) for each group are shown. (B) C57BL/6 mice (n = 5) were injected with graded numbers of male CpG-matured MDC (gray bars) or PDCs (black bars) and boosted after 1 wk with UV-inactivated vaccinia-UTY246–254 minigene. CTL responses were assessed in the blood by ex vivo tetramer staining 8 d after boosting. Tetramer stainings of control mice, primed by female MDC or by vaccinia-UTY246–254 minigene alone, are shown (white bars).

Mentions: Fig. S1 shows the phenotype of immature and CpG-matured PDCs and MDCs isolated from FLT3-L–supplemented bone marrow cultures. Fig. S2 supplements Fig. 1 and shows priming of SMCY738–746-specific CTLs by CpG-matured PDCs. Fig. S3 shows the phenotype of immature and CpG-matured PDCs differentiated from type I IFN receptor–deficient mice (129A) and wild-type 129 S1 mice. Fig. S4 supplements Fig. 10 and shows priming of OVA257–264-specific CTLs by peptide-pulsed mature PDCs. Online supplemental material is available at http://www.jem.org/cgi/content/full/jem.20031059/DC1.


CpG-matured murine plasmacytoid dendritic cells are capable of in vivo priming of functional CD8 T cell responses to endogenous but not exogenous antigens.

Salio M, Palmowski MJ, Atzberger A, Hermans IF, Cerundolo V - J. Exp. Med. (2004)

Intravenous injection of CpG-matured male PDCs induces CTL responses. (A) C57BL/6 mice (n = 5) were injected i.v. with 105 male MDC or PDCs, immature or CpG matured. Control animals were injected with female MDC. CTL responses were assessed in the blood by ex vivo FACS® analysis using UTY246–254-H-2-Db tetramers 7 d after priming. Mean proportions of tetramer+ cells as a percentage of CD8 cells (± SEM) for each group are shown. (B) C57BL/6 mice (n = 5) were injected with graded numbers of male CpG-matured MDC (gray bars) or PDCs (black bars) and boosted after 1 wk with UV-inactivated vaccinia-UTY246–254 minigene. CTL responses were assessed in the blood by ex vivo tetramer staining 8 d after boosting. Tetramer stainings of control mice, primed by female MDC or by vaccinia-UTY246–254 minigene alone, are shown (white bars).
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Related In: Results  -  Collection

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fig1: Intravenous injection of CpG-matured male PDCs induces CTL responses. (A) C57BL/6 mice (n = 5) were injected i.v. with 105 male MDC or PDCs, immature or CpG matured. Control animals were injected with female MDC. CTL responses were assessed in the blood by ex vivo FACS® analysis using UTY246–254-H-2-Db tetramers 7 d after priming. Mean proportions of tetramer+ cells as a percentage of CD8 cells (± SEM) for each group are shown. (B) C57BL/6 mice (n = 5) were injected with graded numbers of male CpG-matured MDC (gray bars) or PDCs (black bars) and boosted after 1 wk with UV-inactivated vaccinia-UTY246–254 minigene. CTL responses were assessed in the blood by ex vivo tetramer staining 8 d after boosting. Tetramer stainings of control mice, primed by female MDC or by vaccinia-UTY246–254 minigene alone, are shown (white bars).
Mentions: Fig. S1 shows the phenotype of immature and CpG-matured PDCs and MDCs isolated from FLT3-L–supplemented bone marrow cultures. Fig. S2 supplements Fig. 1 and shows priming of SMCY738–746-specific CTLs by CpG-matured PDCs. Fig. S3 shows the phenotype of immature and CpG-matured PDCs differentiated from type I IFN receptor–deficient mice (129A) and wild-type 129 S1 mice. Fig. S4 supplements Fig. 10 and shows priming of OVA257–264-specific CTLs by peptide-pulsed mature PDCs. Online supplemental material is available at http://www.jem.org/cgi/content/full/jem.20031059/DC1.

Bottom Line: In vitro experiments have shown that upon maturation, human and murine PDCs develop into potent immunostimulatory cells; however, their ability to prime an immune response in vivo remains to be addressed.In contrast, immature PDCs are unable to prime antigen-specific CTLs.Our results underline the heterogeneity and plasticity of different antigen-presenting cells, and reveal an important role of mature PDCs in priming CD8 responses to endogenous antigens, in addition to their previously reported ability to modulate antiviral responses via type I IFN.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research Tumor Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headley Way, OX3 9DS Oxford, UK. mariolina.salio@imm.ox.ac.uk

ABSTRACT
Plasmacytoid dendritic cells (PDCs) are a unique leukocyte population capable of secreting high levels of type I interferon (IFN) in response to viruses and bacterial stimuli. In vitro experiments have shown that upon maturation, human and murine PDCs develop into potent immunostimulatory cells; however, their ability to prime an immune response in vivo remains to be addressed. We report that CpG-matured murine PDCs are capable of eliciting in naive mice antigen-specific CTLs against endogenous antigens as well as exogenous peptides, but not against an exogenous antigen. Type I IFN is not required for priming, as injection of CpG-matured PDCs into type I IFN receptor-deficient mice elicits functional CTL responses. Mature PDCs prime CTLs that secrete IFN-gamma and protect mice from a tumor challenge. In contrast, immature PDCs are unable to prime antigen-specific CTLs. However, mice injected with immature PDCs are fully responsive to secondary antigenic challenges, suggesting that PDCs have not induced long-lasting tolerance via anergic or regulatory T cells. Our results underline the heterogeneity and plasticity of different antigen-presenting cells, and reveal an important role of mature PDCs in priming CD8 responses to endogenous antigens, in addition to their previously reported ability to modulate antiviral responses via type I IFN.

Show MeSH
Related in: MedlinePlus