A Subset of Toll-Like Receptor Ligands Induces Cross-presentation by Bone Marrow-Derived Dendritic Cells

Datta, Sandip K.; Redecke, Vanessa; Prilliman, Kiley R.; Takabayashi, Kenji; Corr, Maripat; Tallant, Thomas C.; DiDonato, Joseph; Dziarski, Roman; Akira, Shizuo; Schoenberger, Stephen P.; Raz, Eyal

doi:10.4049/jimmunol.170.8.4102

Cited by 275 publications

(242 citation statements)

References 56 publications

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“…Our results are in contrast with previous observations made with model antigens, such as OVA, where a strong dependence of cross-presentation on TLR signaling was observed [22,37]. Multiple reasons may be responsible for the observed differences.…”

Section: Discussioncontrasting

confidence: 99%

“…VLP are recognized by natural antibodies and presumably trigger the classical as well as the alternative pathway of complement activation. Hence, Fc as well as complement receptors may be likely candidates for at least partial activation of DC in the absence of IFN-a/bR signaling.In support of this notion, CD86 upregulation but not CCR7 expression was impaired in IFN-a/bR À/À mice in response to RNA virus, suggesting a unique dissociation of migration and maturation events in DC responding to RNA [36].Our results are in contrast with previous observations made with model antigens, such as OVA, where a strong dependence of cross-presentation on TLR signaling was observed [22,37]. Multiple reasons may be responsible for the observed differences.…”

supporting

confidence: 62%

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Innate signaling regulates cross‐priming at the level of DC licensing and not antigen presentation

Keller¹,

Schwarz²,

Manolova³

et al. 2009

Eur J Immunol

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Innate stimuli, such as TLR ligands, are known to greatly facilitate cross-priming. Currently it is unclear whether innate stimuli enhance cross-priming at the level of crosspresentation or at the level of T-cell priming. In this study, we addressed this question by measuring cross-presentation as well as cross-priming by virus-like particles (VLP) displaying peptide p33 derived of lymphocytic choriomeningitis virus. Innate stimuli were varied by either packaging different TLR ligands into virus-like particles or using mice deficient in two key molecules of TLR-signaling, namely the adaptor molecule MyD88 as well as IFN-a/b receptor. While efficient cross-presentation occurred despite strongly reduced activation of DC in the absence of TLR ligand-mediated signals, T-cell priming was abolished. Thus, innate stimuli regulate cross-priming at the level of DC licensing for T-cell activation and not antigen presentation.Key words: Antigen presentation/processing . Cross-presentation/priming . DC Introduction CD8 1 T cells play an important role in defense against infectious agents. Activated CD8 1 T cells differentiate into CTL that kill infected cells. CTL recognize endogenously synthesized antigenic peptides complexed with MHC class I molecules on the surface of APC. Since not all pathogens directly infect APC, it is necessary that APC are able to internalize exogenous antigens and present them on MHC class I molecules for CD8 1 T-cell recognition, a process known as cross-presentation [1][2][3]. Such cross-presented antigens may make an important contribution to the induction of CTL responses, in particular for non-replicating antigens, such as virus-like particles (VLP) [4]. The main cell types involved in cross-presentation are professional APC, such as DC [5,6] as well as macrophages [7,8] but not B cells [9].The primary function of immature DC is to sample foreign antigens for T-cell and perhaps B-cell priming. To this end, DC either sit at strategic positions within lymphoid organs or act as sentinels in peripheral tissues. In any event, for optimal T-cell priming, DC need pathogen-derived signals in order to mature [10]. In a first step, DC are activated by various pathogen-derived molecules (known as PAMP), including ligands for TLR, lectins, intracellular nucleotide-binding oligomerization domain receptors or retinoic acid induced gene [11][12][13][14]. So far 11 TLR have been identified in mice [15]. TLR recognize invariant viral or bacterial structures. A number of receptors are specialized in recognizing nucleic acids, such as dsRNA (TLR3), ssRNA (TLR7 and TLR8), and DNA rich in non-methlylated CG motifs (CpG, TLR9). The interaction of microbial ligands with innate immune system receptors initiates the maturation of DC. Stimulation of DC with such innate stimuli results in licensed DC. Such DC express intermediate levels of cell surface costimulatory molecules. Endogenous mediators, such as TNF family members, chemokines, or other cytokines facilitate the full differentiation of DC, expressing high leve...

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Section: Discussioncontrasting

confidence: 99%

supporting

confidence: 62%

Innate signaling regulates cross‐priming at the level of DC licensing and not antigen presentation

Keller¹,

Schwarz²,

Manolova³

et al. 2009

Eur J Immunol

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“…This finding was somewhat surprising in view of the recent report by Datta et al [34], in which CpG-induced cross-priming of OVA by DC in their system was TAP dependent and inhibited by lactacystin. The explanation for these different results in the same OVA system is unclear but could be related to small technical differences in isolation and test procedures, as DC are highly active cells in early cultures.…”

Section: Discussionmentioning

confidence: 67%

Alternative processing for MHC class I presentation by immature and CpG‐activated dendritic cells

Chen

Jondal

2004

Eur J Immunol

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Exogenous proteins can be processed by antigen-presenting cells for the generation of MHC class I-restricted T cell responses. Where this occurs is not clear, although both transfer of internalized antigen into the cytosol and alternative processing in endolysosomes and phagosomes have been reported. Here we have studied the capacity of bone marrowderived mouse myeloid dendritic cells (DC) to process the OVA protein for peptide presentation by H2-K b . We have found that immature DC (iDC), both wild-type and transporter associated with antigen processing (TAP)-deficient cells, can transiently process OVA in a pathway which is resistant to inhibitors of the classical MHC class I pathway including the Golgi inhibitor Brefeldin A (BFA) and the proteasome inhibitor lactacystin. This alternative pathway is not found in subcultured DC with an intermediate maturity (imDC) or in resting, IL-3 expanded macrophages but can be re-expressed in imDC if these are activated by an immunostimulatory CpG oligonucleotide. Both iDC and CpG-activated DC were found to process OVA by regurgitation. In addition, we found that iDC secrete proteolytic enzymes into the supernatant, which can process OVA in the extracellular phase. These results suggest that multiple pathways exist for the processing of exogenous protein antigens into MHC class Ibinding peptides.

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“…Combination of gemcitabine with anti-CD40 mAb led to complete cure of these tumors (36). Moreover, not only expression of costimulatory molecules, but also Ag presentation by DC is enhanced after activation of the DC by CpG sequences (37). In addition, a combination of an Ag with CpG sequences was shown to lead to CD11c ϩ cells that were capable of eliciting protective immunity in naive mice in the absence of further Ag or adjuvant (38).…”

Section: Discussionmentioning

confidence: 97%

Activation of Dendritic Cells That Cross-Present Tumor-Derived Antigen Licenses CD8+ CTL to Cause Tumor Eradication

Mierlo¹,

Boonman

Dumortier³

et al. 2004

The Journal of Immunology

153

124

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The fate of naive CD8+ T cells is determined by the environment in which they encounter MHC class I presented peptide Ags. The manner in which tumor Ags are presented is a longstanding matter of debate. Ag presentation might be mediated by tumor cells in tumor draining lymph nodes or via cross-presentation by professional APC. Either pathway is insufficient to elicit protective antitumor immunity. We now demonstrate using a syngeneic mouse tumor model, expressing an Ag derived from the early region 1A of human adenovirus type 5, that the inadequate nature of the antitumor CTL response is not due to direct Ag presentation by the tumor cells, but results from presentation of tumor-derived Ag by nonactivated CD11c+ APC. Although this event results in division of naive CTL in tumor draining lymph nodes, it does not establish a productive immune response. Treatment of tumor-bearing mice with dendritic cell-stimulating agonistic anti-CD40 mAb resulted in systemic efflux of CTL with robust effector function capable to eradicate established tumors. For efficacy of anti-CD40 treatment, CD40 ligation of host APC is required because adoptive transfer of CD40-proficient tumor-specific TCR transgenic CTL into CD40-deficient tumor-bearing mice did not lead to productive antitumor immunity after CD40 triggering in vivo. CpG and detoxified LPS (MPL) acted similarly as agonistic anti-CD40 mAb with respect to CD8+ CTL efflux and tumor eradication. Together these results indicate that dendritic cells, depending on their activation state, orchestrate the outcome of CTL-mediated immunity against tumors, leading either to an ineffective immune response or potent antitumor immunity.

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A Subset of Toll-Like Receptor Ligands Induces Cross-presentation by Bone Marrow-Derived Dendritic Cells

Cited by 275 publications

References 56 publications

Innate signaling regulates cross‐priming at the level of DC licensing and not antigen presentation

Innate signaling regulates cross‐priming at the level of DC licensing and not antigen presentation

Alternative processing for MHC class I presentation by immature and CpG‐activated dendritic cells

Activation of Dendritic Cells That Cross-Present Tumor-Derived Antigen Licenses CD8+ CTL to Cause Tumor Eradication

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