Development of antigen cross-presentation capacity in dendritic cells

Dresch, C; Leverrier, Yann; Marvel, Jacqueline; Shortman, Ken

doi:10.1016/j.it.2012.04.009

Cited by 60 publications

(53 citation statements)

References 61 publications

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“…The conventional CD8a þ DC subset is the key DC population inducing T-cell responses against viral or tumor antigens due to its ability to cross-present exogenous antigen on MHC-I molecules to CD8 þ T cells. 30 To assess the impact of RLH-induced cell death on DC activation, we isolated DC populations from mice, in which DCs were in vivo expanded by Flt3L secreting B16 cells. 31 This allowed us to investigate conventional CD8a þ and CD8a À CD11c high DCs, as well as B220 þ CD11c þ plasmacytoid DCs (pDCs) (Figure 3a).…”

Section: Resultsmentioning

confidence: 99%

RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells

et al. 2014

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Pancreatic cancer is characterized by a microenvironment suppressing immune responses. RIG-I-like helicases (RLH) are immunoreceptors for viral RNA that induce an antiviral response program via the production of type I interferons (IFN) and apoptosis in susceptible cells. We recently identified RLH as therapeutic targets of pancreatic cancer for counteracting immunosuppressive mechanisms and apoptosis induction. Here, we investigated immunogenic consequences of RLH-induced tumor cell death. Treatment of murine pancreatic cancer cell lines with RLH ligands induced production of type I IFN and proinflammatory cytokines. In addition, tumor cells died via intrinsic apoptosis and displayed features of immunogenic cell death, such as release of HMGB1 and translocation of calreticulin to the outer cell membrane. RLH-activated tumor cells led to activation of dendritic cells (DCs), which was mediated by tumor-derived type I IFN, whereas TLR, RAGE or inflammasome signaling was dispensable. Importantly, CD8aþ DCs effectively engulfed apoptotic tumor material and cross-presented tumorassociated antigen to naive CD8 þ T cells. In comparison, tumor cell death mediated by oxaliplatin, staurosporine or mechanical disruption failed to induce DC activation and antigen presentation. Tumor cells treated with sublethal doses of RLH ligands upregulated Fas and MHC-I expression and were effectively sensitized towards Fas-mediated apoptosis and cytotoxic T lymphocyte (CTL)-mediated lysis. Vaccination of mice with RLH-activated tumor cells induced protective antitumor immunity in vivo. In addition, MDA5-based immunotherapy led to effective tumor control of established pancreatic tumors. In summary, RLH ligands induce a highly immunogenic form of tumor cell death linking innate and adaptive immunity.

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Section: Resultsmentioning

confidence: 99%

RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells

et al. 2014

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“…It was proposed that GM-CSF-induced upregulation of CD103 on CD8α + DCs may be the cause for enhanced cross-presentation, whereas enhanced antigen uptake was not found to be responsible for the GM-CSF effect [8]. However, there is no formal evidence that CD103 expression is required for cross-presentation [9]. The results presented here, that GM-CSF induces CCL17 expression in splenic DCs, together with our previous findings that CCL17 enhances cross-priming by promoting the attraction of CD8 + T cells [16], may offer a novel mechanistic explanation how GM-CSF enhances the cross-presenting ability of DCs.…”

Section: Discussionmentioning

confidence: 99%

“…Under inflammatory conditions monocytes are able to differentiate into mature DCs through the recognition of PAMPs in conjunction with GM-CSF (Csf-2) [5,6]. GM-CSF has been implicated in the formation of inflammatory DCs in vivo [7], and was also shown to enhance CD103 expression and the ability of CD8α + DCs to cross-present antigens to CD8 + T cells [8][9][10].Besides the classification of DC subsets on the basis of surface phenotype and migratory abilities, there is evidence that the local organ-specific microenvironment also has distinct influences on DC function even in phenotypically similar DC subsets. At the level of transcriptional profiling this has been indicated by direct comparison of defined DC subsets from different lymphoid organs [11].…”

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confidence: 99%

Cytokine‐dependent regulation of dendritic cell differentiation in the splenic microenvironment

et al. 2013

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The DC-derived chemokine CCL17, a ligand of CCR4, has been shown to promote various inflammatory diseases such as atopic dermatitis, atherosclerosis, and inflammatory bowel disease. Under steady-state conditions, and even after systemic stimulation with LPS, CCL17 is not expressed in resident splenic DCs as opposed to CD8α − CD11b + LN DCs, which produce large amounts of CCL17 in particular after maturation. Upon systemic NKT cell activation through α-galactosylceramide stimulation however, CCL17 can be upregulated in both CD8α − and CD8α + splenic DC subsets and enhances crosspresentation of exogenous antigens. Based on genome-wide expression profiling, we now show that splenic CD11b + DCs are susceptible to IFN-γ-mediated suppression of CCL17, whereas LN CD11b + CCL17 + DCs downregulate the IFN-γR and are much less responsive to IFN-γ. Under inflammatory conditions, particularly in the absence of IFN-γ signaling in IFN-γRKO mice, CCL17 expression is strongly induced in a major proportion of splenic DCs by the action of GM-CSF in concert with IL-4. Our findings demonstrate that the local cytokine milieu and differential cytokine responsiveness of DC subsets regulate lymphoid organ specific immune responses at the level of chemokine expression.Keywords: DCs r GM-CSF r IFN-γ receptor r IL-4 r Spleen Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDCs are important sentinels of the immune system. Based on their developmental origin, surface phenotype, and mobility, DCs can be subdivided into several major subsets, such as plasmacytoid Correspondence: Prof. Irmgard Förster e-mail: irmgard.foerster@uni-bonn.deDCs, resident DCs of lymphoid organs, and migratory DC subsets, which are mainly found in nonlymphoid tissues and their local draining LN [1]. In the lamina propria of the gut and in MLN, CD103 + CD11b + DCs were identified as the major migratory DC subset with potency to induce both tolerance and immunity * These authors contributed equally to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 500-510 Immunomodulation 501 [2,3]. In contrast to visceral and peripheral LN (PLN), the spleen harbors mainly lymphoid organ resident DCs with the exception of circulating plasmacytoid DCs [4]. Under inflammatory conditions monocytes are able to differentiate into mature DCs through the recognition of PAMPs in conjunction with GM-CSF (Csf-2) [5,6]. GM-CSF has been implicated in the formation of inflammatory DCs in vivo [7], and was also shown to enhance CD103 expression and the ability of CD8α + DCs to cross-present antigens to CD8 + T cells [8][9][10].Besides the classification of DC subsets on the basis of surface phenotype and migratory abilities, there is evidence that the local organ-specific microenvironment also has distinct influences on DC function even in phenotypically similar DC subsets. At the level of transcriptional profiling this has been indicated by direct comparison of...

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“…[1][2][3] cDCs have outstanding capacity to prime naive T cells to generate various types of effector T (T eff ) cells owing to the prominent expression of major histocompatibility complex class (MHC) II and costimulatory molecues. [4][5][6] On the other hand, pDCs are specialized in endosomal TLR7/9-mediated recognition of viral nucleic acids (NAs) and respond with the massive secretion of type I interferon (IFN-I). [7][8][9] Therefore, pDCs have been considered as important mediators of antiviral responses.…”

Section: Introductionmentioning

confidence: 99%

Crucial role of plasmacytoid dendritic cells in the development of acute colitis through the regulation of intestinal inflammation

et al. 2017

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Development of antigen cross-presentation capacity in dendritic cells

Cited by 60 publications

References 61 publications

RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells

RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells

Cytokine‐dependent regulation of dendritic cell differentiation in the splenic microenvironment

Crucial role of plasmacytoid dendritic cells in the development of acute colitis through the regulation of intestinal inflammation

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