Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery

Schnurr, Max; Chen, Qiyuan; Shin, Amanda; Chen, Weisan; Toy, Tracey; Jenderek, C; Green, Simon; Miloradovic, Lena; Drane, Debbie; Davis, Ian D.; Villadangos, José A; Shortman, Ken; Maraskovsky, Eugene; Cebon, Jonathan

doi:10.1182/blood-2004-08-3105

Cited by 173 publications

(170 citation statements)

References 44 publications

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“…This amount of OVA was also the minimum required to detect presentation via MHC class II to OT-II cells. This finding contrasts with previous reports that used soluble antigen to assess the cross-presenting capacity of mouse bone marrow-derived or human monocyte-derived DC, which concluded that the concentration of antigen that was required for cross-presentation was high and probably nonphysiological (32)(33)(34)(35)(36)(37). Our results thus demonstrate that crosspresentation is a highly efficient process in the CD8 ϩ DC population.…”

Section: Presentation Of Cell-associated Antigen By Splenic DC Populacontrasting

confidence: 99%

The dominant role of CD8⁺dendritic cells in cross-presentation is not dictated by antigen capture

Schnorrer¹,

Behrens²,

Wilson

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Mouse spleens contain three populations of conventional (CD11c high ) dendritic cells (DCs) that play distinct functions. The CD8 ؉ DC are unique in that they can present exogenous antigens on their MHC class I molecules, a process known as cross-presentation. It is unclear whether this special ability is because only the CD8 ؉ DC can capture the antigens used in cross-presentation assays, or because this is the only DC population that possesses specialized machinery for cross-presentation. To solve this important question we examined the splenic DC subsets for their ability to both present via MHC class II molecules and cross-present via MHC class I using four different forms of the model antigen ovalbumin (OVA). These forms include a cell-associated form, a soluble form, OVA expressed in bacteria, or OVA bound to latex beads. With the exception of bacterial antigen, which was poorly cross-presented by all DC, all antigenic forms were cross-presented much more efficiently by the CD8 ؉ DC. This pattern could not be attributed simply to a difference in antigen capture because all DC subsets presented the antigen via MHC class II. Indeed, direct assessments of endocytosis showed that CD8 ؉ and CD8 ؊ DC captured comparable amounts of soluble and bead-associated antigen, yet only the CD8 ؉ DC cross-presented these antigenic forms. Our results indicate that cross-presentation requires specialized machinery that is expressed by CD8 ؉ DC but largely absent from CD8 ؊ DC. This conclusion has important implications for the design of vaccination strategies based on antigen targeting to DC.antigen presentation ͉ mice ͉ endocytosis ͉ ovalbumin ͉ vaccines D endritic cells (DC) possess several mechanisms that make them highly efficient antigen-presenting cells. DC can endocytose a large variety of exogenous antigens for presentation via MHC class II molecules and for cross-presentation via MHC class I (1). The cross-presenting capacity of DC is unusual, because most other cell types are only able to present endogenous antigens (i.e., antigens synthesized by the antigenpresenting cells themselves) on their MHC class I molecules. Thus, DC possess specialized machinery, as yet not fully defined, that allows delivery of exogenous antigens into the MHC class I presentation pathway for cross-presentation (2, 3).On the other hand, several populations of DC have been described (4, 5), and it is unclear whether all these DC types can cross-present (6). Mouse spleens contain three ''conventional'' (CD11c high ) DC subsets: CD8 ϩ DC, CD4 ϩ DC, and CD4 Ϫ CD8 Ϫ [double negative (DN)] DC. Previous studies have shown that cell-associated antigen was cross-presented by CD8 ϩ but not CD8 Ϫ DC (7-10). The unique capacity of the CD8 ϩ DC at cross-presenting this form of antigen was attributed to their ability to capture dead cells (7-9, 11, 12) because antigens in soluble or immunocomplexed form, or associated to bacteria, were reportedly cross-presented by both CD8 ϩ and CD8 Ϫ DC (8, 9, 13). These findings led to the hypothesis that all DC can...

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Section: Presentation Of Cell-associated Antigen By Splenic DC Populacontrasting

confidence: 99%

The dominant role of CD8⁺dendritic cells in cross-presentation is not dictated by antigen capture

Schnorrer¹,

Behrens²,

Wilson

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

354

347

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“…It is well conceivable that by both the antigenic load and the pDC activating stimuli encapsulated in these PLGA microparticles, T cell activation and the resulting cytokine profile can be modulated. The ability of human pDCs to cross-present Ags to CD8 + T cells remains controversial (16,51). Whether human pDCs can crosspresent particulate Ags and induce functional CD8 + T cells is yet unknown and needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

Human Plasmacytoid Dendritic Cells Phagocytose, Process, and Present Exogenous Particulate Antigen

Tel

Lambeck

Cruz

et al. 2010

The Journal of Immunology

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“…This so-called ''cross-presentation'' pathway is mainly performed by DC [6,7]. Following the initial observations of cross-priming of T cells by bone-marrowderived cells [8,9], numerous studies investigated the role of cross-priming in the induction of anti-tumor immune responses [10][11][12][13][14] and the strategies to manipulate cross-priming to induce and amplify tumor-specific immune responses [15][16][17][18][19]. Because …”

Section: Introductionmentioning

confidence: 99%

“…Because most studies analyzing cross-presentation in human DC used apoptotic cells or vesicles as the source of antigen [35,36], mechanistic analyses are not fully conclusive. Purified proteins or peptides, however, have also been used in a few studies that provided some insights into the mechanisms required for antigen delivery, processing and presentation by human DC [15,18,19,32,37,38]. In spite of numerous technical difficulties related to the use of human cells, it is critical to better understand the mechanisms and pathways of cross-presentation of antigen formulations that are being used in the clinics.…”

Section: Introductionmentioning

confidence: 99%

Long‐lasting cross‐presentation of tumor antigen in human DC

et al. 2009

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DC cross-present exogenous antigens on MHC class I molecules, a process required for the onset of anti-tumor immune responses. In order to study the cross-presentation of tumor antigens by human DC, we compared the pathways of cross-presentation of long peptides requiring internalization and intracellular processing with the direct presentation of short peptides, which does not require intracellular processing. We found that, after brief incubations with DC, short peptides were presented to CD8 1 T cells with higher efficiencies than long peptides. After longer times of chase in the absence of peptide, however, the efficiency of presentation of the two types of peptides was reversed. After 2-3 days, DC pulsed with long peptides still activated T cells efficiently, while DC pulsed with short peptides failed to do so. Long-lasting presentation of the long peptides was, at least in part, due to a stored persistent pool of antigen, which was still available for loading on MHC class I molecules after several days of chase. These results show that the use of long synthetic peptides allows the efficient, long-lasting, presentation of tumor antigens, suggesting that long peptides represent an interesting approach for active anti-tumor vaccination.Key words: Cross-presentation . CTL . DC . Long peptides . Melanoma-associated antigen Supporting Information available online IntroductionAdaptative immune responses, especially through CD8 1 T cells, can induce the rejection of solid tumors [1][2][3]. Endogenously expressed tumor-associated antigens (TAA) expressed in tumor cells are recognized by CTL through cognate interactions of the TCR with class I MHC molecules associated with 8-10 amino acid long antigenic peptides. These tumor cell/T-cell interactions, however, are not sufficient to activate naïve T lymphocytes and to induce a memory response. Indeed, professional APC are required for the induction of effector and memory tumor-specific immune responses [4,5]. As most often APC do not endogenously express TAA, uptake and presentation of antigen via an exogenous pathway is required. This so-called ''cross-presentation'' pathway is mainly performed by DC [6,7]. Following the initial observations of cross-priming of T cells by bone-marrowderived cells [8,9], numerous studies investigated the role of cross-priming in the induction of anti-tumor immune responses [10][11][12][13][14] and the strategies to manipulate cross-priming to induce and amplify tumor-specific immune responses [15][16][17][18][19]. Because 380they display a unique capacity to efficiently cross-present exogenous antigens and to prime naïve CD8 1 T cells, DC are good candidates for cancer immunotherapy. The DC-based cancer vaccines that have been tested successfully in mouse models include DC loaded with different forms of tumor antigens, including short peptides, tumor extracts, tumor-derived membrane vesicles and tumor-derived RNA [20][21][22][23]. Nevertheless, these cell-based vaccines present some disadvantages, mainly related to their cost and the...

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Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery

Cited by 173 publications

References 44 publications

The dominant role of CD8⁺dendritic cells in cross-presentation is not dictated by antigen capture

The dominant role of CD8⁺dendritic cells in cross-presentation is not dictated by antigen capture

Human Plasmacytoid Dendritic Cells Phagocytose, Process, and Present Exogenous Particulate Antigen

Long‐lasting cross‐presentation of tumor antigen in human DC

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Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery

Cited by 173 publications

References 44 publications

The dominant role of CD8+dendritic cells in cross-presentation is not dictated by antigen capture

The dominant role of CD8+dendritic cells in cross-presentation is not dictated by antigen capture

Human Plasmacytoid Dendritic Cells Phagocytose, Process, and Present Exogenous Particulate Antigen

Long‐lasting cross‐presentation of tumor antigen in human DC

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Product

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The dominant role of CD8⁺dendritic cells in cross-presentation is not dictated by antigen capture

The dominant role of CD8⁺dendritic cells in cross-presentation is not dictated by antigen capture