Toll-dependent selection of microbial antigens for presentation by dendritic cells

Blander, J. Magarian; Medzhitov, Ruslan

doi:10.1038/nature04596

Cited by 727 publications

(646 citation statements)

References 30 publications

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“…This phenotype was the consequence of a defect in the delivery of lysosomal proteases to phagosomes, as well as a delay of fusion of phagosomes with lysosomes. The precise mechanism of how the macroautophagy machinery is recruited to phagosomes and might enhance fusion with lysosomes remains unclear, but these findings are in line with previous studies, documenting enhanced antigen presentation of TLR ligand coated antigen and Atg supported fusion of phagosomes containing such antigen with lysosomes [39][40] . In one of these studies, the authors described that TLR engagement induces "LC3-associated phagocytosis" (LAP).…”

Section: Endogenous Pathwaysupporting

confidence: 85%

MHC presentation via autophagy and how viruses escape from it

Gannagé

Münz

2010

Semin Immunopathol

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T cells detect infected and transformed cells via antigen presentation by major histocompatibility complex (MHC) molecules on the cell surface. For T cell stimulation, these MHC molecules present fragments of proteins that are expressed or taken up by the cell. These fragments are generated by distinct proteolytic mechanisms for presentation on MHC class I molecules to cytotoxic CD8(+) and on MHC class II molecules to helper CD4(+) T cells. Proteasomes are primarily involved in MHC class I ligand and lysosomes, in MHC class II ligand generation. Autophagy delivers cytoplasmic material to lysosomes and, therefore, contributes to cytoplasmic antigen presentation by MHC class II molecules. In addition, it has been recently realized that this process also supports extracellular antigen processing for MHC class II presentation and cross-presentation on MHC class I molecules. Although the exact mechanisms for the regulation of these antigen processing pathways by autophagy are still unknown, recent studies, summarized in this review, suggest that they contribute to immune responses against infections and to maintain tolerance. Moreover, they are targeted by viruses for immune escape and could maybe be harnessed for immunotherapy. These fragments are generated by distinct proteolytic mechanisms for presentation on MHC class I molecules to cytotoxic CD8 + and on MHC class II molecules to helper CD4 + T cells.Proteasomes are primarily involved in MHC class I ligand, and lysosomes in MHC class II ligand generation. Autophagy delivers cytoplasmic material to lysosomes, and, therefore, contributes to cytoplasmic antigen presentation by MHC class II molecules. In addition, it has been recently realized that this process also supports extracellular antigen processing for MHC class II presentation and cross-presentation on MHC class I molecules. Although the exact mechanisms for the regulation of these antigen processing pathways by autophagy are still unknown, recent studies, summarized in this review, suggest that they contribute to immune responses against infections and to maintain tolerance. Moreover, they are targeted by viruses for immune escape, and could maybe be harnessed for immunotherapy. Gannage and Münz 3

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Section: Endogenous Pathwaysupporting

confidence: 85%

MHC presentation via autophagy and how viruses escape from it

Gannagé

Münz

2010

Semin Immunopathol

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“…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: 61%

“…Maturation of DC is a key step for the regulation of immune responses, as resting DC appear to induce T-cell tolerance whereas only activated DC induce T-cell activation [20,21]. Furthermore, TLR signaling has been shown to promote phagocytosis by DC as well as endosomal maturation, facilitating antigen processing and presentation [22]. Most TLR share the common adaptor molecule MyD88 to activate nuclear translocation of NF-kB and the production of cytokines including .…”

mentioning

confidence: 99%

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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“…First, TLRs trigger the secretion of critical cytokines such as IL1, IL-6 and IL-12 by DCs, which are important for T-cell differentiation and the induction of potent adaptive immunity. Several groups have shown that conjugation of certain TLR ligands (that is, for TLR2, TLR4, TLR7 and TLR9) to peptides or proteins significantly enhances CD4 þ and CD8 þ T-cell responses compared with administration of TLR ligands or a peptide/protein mixture alone (Jackson et al, 2004;Wille-Reece et al, 2005;Blander and Medzhitov, 2006). Third, TLRs can directly stimulate the proliferation of CD4 þ and CD8 þ T cells as well as reverse the suppressive function of Treg cells (Crellin et al, 2005;Peng et al, 2005;Tabiasco et al, 2006).…”

Section: Targeting Tlrs For Cancer Therapymentioning

confidence: 99%