Dendritic cells process exogenous viral proteins and virus‐like particles for class I presentation to CD8<sup>+</sup> cytotoxic T lymphocytes

Bachmann, Martin F.; Lutz, Manfred B.; Layton, Guy T.; Harris, Stephen; Fehr, Thomas; Rescigno, María; Ricciardi‐Castagnoli, Paola

doi:10.1002/eji.1830261109

Cited by 140 publications

(94 citation statements)

References 36 publications

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“…However, the same VLPs applied together with CpGs or anti-CD40 Abs were able to induce CTL responses comparable to those observed after immunization with live viral vectors. M and DCs are known to be able to cross-present VLPs and other particulate Ags (5,15,53,54). This was confirmed in this study, because ex vivo-isolated DCs and M efficiently processed p33-VLPs for MHC class I-associated presentation.…”

Section: Discussionsupporting

confidence: 84%

Critical Role for Activation of Antigen-Presenting Cells in Priming of Cytotoxic T Cell Responses After Vaccination with Virus-Like Particles

Storni¹,

Lechner²,

Erdmann³

et al. 2002

The Journal of Immunology

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113

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Virus-like particles (VLPs) are known to induce strong Ab responses in the absence of adjuvants. In addition, VLPs are able to prime CTL responses in vivo. To study the efficiency of this latter process, we fused peptide p33 derived from lymphocytic choriomeningitis virus to the hepatitis B core Ag, which spontaneously assembles into VLPs (p33-VLPs). These p33-VLPs were efficiently processed in vitro and in vivo for MHC class I presentation. Nevertheless, p33-VLPs induced weak CTL responses that failed to mediate effective protection from viral challenge. However, if APCs were activated concomitantly in vivo using either anti-CD40 Abs or CpG oligonucleotides, the CTL responses induced were fully protective against infection with lymphocytic choriomeningitis virus or recombinant vaccinia virus. Moreover, these CTL responses were comparable to responses generally induced by live vaccines, because they could be measured in primary ex vivo 51Cr release assays. Thus, while VLPs alone are inefficient at inducing CTL responses, they become very powerful vaccines if applied together with substances that activate APCs.

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Section: Discussionsupporting

confidence: 84%

Critical Role for Activation of Antigen-Presenting Cells in Priming of Cytotoxic T Cell Responses After Vaccination with Virus-Like Particles

Storni¹,

Lechner²,

Erdmann³

et al. 2002

The Journal of Immunology

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113

111

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“…Here, we show that VLP-p33 were efficiently cross-presented by DC, confirming earlier reports [35]. Interestingly, we found normal cross-presentation of VLP-p33 in the absence of TLR7/8, MyD88 or IFN-a/bR signaling.…”

Section: Discussionsupporting

confidence: 92%

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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“…In contrast, extracellular Ags are presented in class II MHC and lead to a humoral response. Increasing evidence suggests there is cross-talk between these two pathways and that exogenous proteins are processed for presentation via the same pathway described for conventional MHC class I-restricted cytosolic Ags (44,45). The immune signals that regulate this cross-priming are not well understood.…”

Section: Discussionmentioning

confidence: 99%

APC Stimulated by CpG Oligodeoxynucleotide Enhance Activation of MHC Class I-Restricted T Cells

Warren

Bhatia

Acosta

et al. 2000

The Journal of Immunology

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Oligonucleotides containing unmethylated CpG motifs (cytosine-phosphorothioate-guanine oligodeoxynucleotide (CpG ODN)) are potent immunostimulatory agents capable of enhancing the Ag-specific Th1 response when used as immune adjuvants. We evaluated the cellular mechanisms responsible for this effect. Development of a CTL response was enhanced when mice were immunized with peptide-pulsed dendritic cells (DCs) treated with CpG ODN. However, in vitro, CpG ODN had no direct effect on highly purified T cells. In vitro, CpG ODN treatment of peptide- or protein-pulsed DCs enhanced the ability of the DCs to activate class I-restricted T cells. The presence of helper T cells enhanced this effect, indicating that treatment with CpG ODN does not obviate the role of T cell help. The enhanced ability of CpG ODN-treated DCs to activate T cells was present but blunted when DCs derived from IL-12 knockout mice were used. Fixation of Ag-pulsed, CpG ODN-treated DCs limited their ability to activate T cells. In contrast, fixation had little effect on DC activation of T cells when DCs were not exposed to CpG ODN. This indicates that production of soluble factors by DCs stimulated with CpG ODN plays a particularly important role in their ability to activate class I-restricted T cells. We conclude that CpG ODN enhances the development of a cellular immune response by stimulating APCs such as DCs, to produce IL-12 and other soluble factors.

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Dendritic cells process exogenous viral proteins and virus‐like particles for class I presentation to CD8⁺ cytotoxic T lymphocytes

Cited by 140 publications

References 36 publications

Critical Role for Activation of Antigen-Presenting Cells in Priming of Cytotoxic T Cell Responses After Vaccination with Virus-Like Particles

Critical Role for Activation of Antigen-Presenting Cells in Priming of Cytotoxic T Cell Responses After Vaccination with Virus-Like Particles

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

APC Stimulated by CpG Oligodeoxynucleotide Enhance Activation of MHC Class I-Restricted T Cells

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Dendritic cells process exogenous viral proteins and virus‐like particles for class I presentation to CD8+ cytotoxic T lymphocytes

Cited by 140 publications

References 36 publications

Critical Role for Activation of Antigen-Presenting Cells in Priming of Cytotoxic T Cell Responses After Vaccination with Virus-Like Particles

Critical Role for Activation of Antigen-Presenting Cells in Priming of Cytotoxic T Cell Responses After Vaccination with Virus-Like Particles

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

APC Stimulated by CpG Oligodeoxynucleotide Enhance Activation of MHC Class I-Restricted T Cells

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Dendritic cells process exogenous viral proteins and virus‐like particles for class I presentation to CD8⁺ cytotoxic T lymphocytes