Phagocytic processing of bacterial antigens for class I MHC presentation to T cells

Pfeifer, John D.; Wick, Mary Jo; Roberts, Richard L.; Findlay, Kirk; Normark, Staffan

doi:10.1038/361359a0

Cited by 571 publications

(455 citation statements)

References 31 publications

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“…However, precise events at molecular level that are responsible for GM-CSFenhanced cross-presentation by CD8 1 DCs are currently unknown. There are many pathways leading to cross-presentation of antigens [23]: phagosome-to-cytosol [24], endosome-to-ER, ER-phagosome fusion [25,26], endosome-to-ER [27], as well as vacuolar pathway [28,29]. It remains a task to identify which pathway(s) is affected by GM-CSF.…”

Section: Discussionmentioning

confidence: 99%

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8⁺ spleen dendritic cells

et al. 2011

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Resident CD8 1 DCs perform several functions, including cross-presenting antigen and rapidly engulfing the Gram-positive intracellular pathogen Listeria monocytogenes. Little is known about how these functions of CD8 1 DCs are modulated. Here, we show that granulocyte-macrophage CSF (GM-CSF), a cytokine that exists at low levels at steady state but is elevated during infection and inflammation, enhances cross-presentation and rapid uptake of L. monocytogenes by resident CD8 1 DCs. This previously unrecognized functional enhancement of CD8 1 DCs by GM-CSF was independent of promoting DC survival in vitro. Enhancement of these functions by GM-CSF was also marked by CD103 expression on CD8 1 DCs that was strongly regulated by GM-CSF. Our findings not only identify GM-CSF as a key molecule regulating CD8 1 DC function, but also as a factor responsible for functional heterogeneity of CD8 1 DCs that is at least substantially demarcated by CD103 expression.Keywords: CD8 1 DC . CD103 . Cross-presentation . Granulocyte-macrophage colony-stimulating factor . Listeria monocytogenes Supporting Information available online IntroductionDCs found in the spleen can be grossly separated into CD8 1 DCs and CD8 À DCs. The latter includes CD8 À CD4 1 and CD8 À CD4 À conventional DCs and CD45RA 1 plasmacytoid DCs. Different DC subsets have different functions. Notably, the resident CD8 1 DCs show superior capacity for ingesting cell-associated antigens [1], for cross-presenting antigens (i.e. presenting exogenous antigens to CD8 1 T cells) [2][3][4], for the rapid uptake of certain bacterial pathogens [5] and for producing . It has been previously reported that a small proportion of CD8 1 DCs express the integrin CD103 and these CD103-expressing CD8 1 DCs are enriched in cells engulfing cellular antigens and cross-priming CD8 1 T cells [7]. However, it is unclear what regulates the above Ã Co-senior authors. Here, we investigated whether GM-CSF might influence the function of CD8 1 DCs and CD103 expression. Functionally, DCs from GM-CSF transgenic (GMtg) mice had enhanced crosspresentation, whereas in the absence of GM-CSF signaling, crosspresentation was reduced. Rapid uptake of Listeria monocytogenes by CD8 1 DCs was also reduced in the absence of GM-CSF. Phenotypically, we showed that bacterial infection preferentially increased CD103 expression by CD8 1 DCs and this increase was dependent on GM-CSF. Together, our results identify a critical role for GM-CSF in preferentially regulating expression of the integrin CD103 by CD8 1 DCs and in regulating certain functions of CD8 1 DCs. ResultsGM-CSF enhances cross-presentation by CD8 1 DCs GM-CSF is a cytokine that exists at very low levels at steady state but is greatly induced during infection and inflammation [13]. To understand the role of GM-CSF in regulating the functions of CD8 1 DCs, we chose mouse models with GM-CSF overexpression. We first compared the cross-presentation by CD8 1 DCs from GMtg mice and control littermates. When soluble OVA was used as the antigen in vitro, CD...

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Section: Discussionmentioning

confidence: 99%

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8⁺ spleen dendritic cells

et al. 2011

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“…Clonal analysis of MART1-specific CTLs has shown that MART1/T-cell receptor interactions are tightly restricted to HLA-A2, 37 and a recent study found that mature human MoDCs do not efficiently process and present the MART1 [27][28][29][30][31][32][33][34][35] epitope from whole MART1 due to the presence of the immunoproteasome, 38 suggesting that delivery of some whole proteins, including MART1, may not be an effective method of antigen delivery to DCs. Immature DCs express both the standard proteasome and immunoproteasomes.…”

Section: Discussionmentioning

confidence: 99%

“…The presentation of the MART1 [27][28][29][30][31][32][33][34][35] epitope to the HLA-A2 molecule on MoDCs was examined by measuring IFN-␥ production by the CD8 ϩ T cells within the MART1-specific CTL population in response to E. coli-infected DCs. Immature DCs (10 5 cells, either HLA-matched and HLA-mismatched) were incubated with E. coli (at a ratio of 10 bacteria per DC for 16 hr) or pulsed with control peptides (10 g/ml, 1 hr).…”

Section: Antigen Presentation Assaysmentioning

confidence: 99%

“…In order to determine whether this phenomenon was restricted to OVA and murine APC/T-cell interactions, we investigated whether E. coli/LLO could be used to deliver the MART1 antigen to the MHC class I processing pathways of human DCs. Full-length 357 bp MART1 cDNA, containing the MART1 [27][28][29][30][31][32][33][34][35] HLA-A2-restricted epitope, was cloned into the pCRT7/CT-TOPO inducible expression vector. Inducible expression of MART1 protein was achieved in both native E. coli and E. coli/LLO (Fig.…”

Section: Expression Of the Mart1 Tumour Antigen In E Colimentioning

confidence: 99%

“…As a consequence of the interaction with bacteria, human DCs undergo marked phenotypic and functional maturation. Furthermore, we show that fixed E. coli/ LLO expressing the well-characterised human melanoma antigen, MART1, 20,21 efficiently deliver the HLA-A2-restricted MART1 [27][28][29][30][31][32][33][34][35] epitope for processing and presentation on human MoDCs, suggesting the potential of this system as a novel strategy for human tumour immunotherapy.…”

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confidence: 99%

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Recombinant E. coli efficiently delivers antigen and maturation signals to human dendritic cells: Presentation of MART1 to CD8⁺ T cells

Radford

Jackson

Wang

et al. 2003

Intl Journal of Cancer

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The generation of tumour-specific cytotoxic T-lymphocyte (CTL) responses is the primary focus in the design of immunotherapeutic cancer vaccines. We have recently demonstrated generation of ovalbumin (OVA)-specific CTLs and tumour-protection in a murine tumour model using vaccination with dendritic cells (DCs) pulsed with E. coli expressing listeriolysin O (LLO) and OVA as a model antigen. In this system paraformaldehyde fixation of E. coli/LLO provided an additional safety feature without compromising vaccine efficacy. We therefore reasoned that paraformaldehyde-fixed recombinant E. coli expressing LLO would be an efficient vehicle for the delivery of human tumour antigens to human DCs. In the present study, we demonstrate that fixed E. coli expressing LLO are taken up efficiently by human monocytederived DCs (MoDCs) with minimal toxicity. As a consequence of the interaction with bacteria, human DCs undergo marked phenotypic and functional maturation. Furthermore, we show that fixed E. coli/LLO expressing the well-characterised human melanoma antigen, MART1, efficiently deliver the HLA-A2-restricted MART1 27-35 epitope for processing and presentation on human MoDCs, suggesting the potential of this system as a novel strategy for human tumour immunotherapy. © 2003 Wiley-Liss, Inc. Key words: dendritic cell; E. coli; tumour immunotherapyThe generation of tumour-specific cytotoxic T-lymphocyte (CTL) responses is the primary focus in the design of immunotherapeutic cancer vaccines. It is generally accepted that the initiation of effective antitumour immune responses relies upon antigen-presenting cells (APCs), most notably dendritic cells (DCs), priming CTLs and T helper cells, by processing antigen and presenting it on major histocompatibility (MHC) class I and class II molecules, respectively. DCs are unique in their potent ability to prime naïve T-cell responses, 1,2 and DCs loaded with tumour antigens show increasing potential as vaccine candidates in animal models 3,4 and early-phase clinical trials. [5][6][7][8][9] The generation of appropriate immune responses, and therefore successful vaccination, is highly dependent on the development of effective methods of antigen delivery to DCs. The ideal antigen delivery system should combine efficient processing and presentation of tumour antigens to CD8 ϩ T cells, along with potent DC activation in order to deliver the costimulatory signals necessary for T-cell priming. Preparations of tumour-specific antigens are desirable as less well defined whole tumour cell preparations or lysates contain selfantigens and may result in the induction autoimmunity. In addition, it is desirable to deliver the whole antigen to enable presentation of multiple epitopes without prior knowledge of the patient's HLA haplotype or the nature of the peptide epitopes.A number of vaccine strategies have already been shown to induce potent CTL responses, including infection with recombinant viruses, and DNA or RNA transfection. However, there are safety concerns with the expression of whole a...

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Phagosome dynamics and function

Tjelle¹,

Løvdal²,

Berg³

2000

Bioessays

173

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Phagocytic processing of bacterial antigens for class I MHC presentation to T cells

Cited by 571 publications

References 31 publications

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8⁺ spleen dendritic cells

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8⁺ spleen dendritic cells

Recombinant E. coli efficiently delivers antigen and maturation signals to human dendritic cells: Presentation of MART1 to CD8⁺ T cells

Phagosome dynamics and function

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Phagocytic processing of bacterial antigens for class I MHC presentation to T cells

Cited by 571 publications

References 31 publications

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8+ spleen dendritic cells

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8+ spleen dendritic cells

Recombinant E. coli efficiently delivers antigen and maturation signals to human dendritic cells: Presentation of MART1 to CD8+ T cells

Phagosome dynamics and function

Contact Info

Product

Resources

About

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8⁺ spleen dendritic cells

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8⁺ spleen dendritic cells

Recombinant E. coli efficiently delivers antigen and maturation signals to human dendritic cells: Presentation of MART1 to CD8⁺ T cells