CpG Promotes Cross-Presentation of Dead Cell-Associated Antigens by Pre-CD8α+ Dendritic Cells

Brito, Christelle de; Tomkowiak, Martine; Ghittoni, Raffaella; Caux, Christophe; Leverrier, Yann; Marvel, Jacqueline

doi:10.4049/jimmunol.1001022

Cited by 48 publications

(62 citation statements)

References 52 publications

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“…Interestingly, ipDC also expressed TLR9 (Figure 1b) and, unlike moDC, responded to its ligation by the CpG-containing oligodeoxynucleotide ODN2216 (Supplementary Figure 2d); although expression of TLR9 by CD141 þ DC in human blood and lymphoid tissues was not detected, its expression by CD8a þ DC in the mouse has been described. 10,17 Furthermore, the ligation of TLR3 and TLR9 has been shown to specifically enhance cross-presentation of antigen by mouse DC. 17 --19 In the light of these findings, we investigated expression of the chemokine receptor XCR1.…”

Section: Differentiation Of Clinical-grade DC From Human Ips Cellsmentioning

confidence: 99%

Cross-presentation of tumour antigens by human induced pluripotent stem cell-derived CD141+XCR1+ dendritic cells

Silk

Ichiryu

et al. 2011

Gene Ther

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Monocyte-derived dendritic cells (moDC) have been widely used in cancer immunotherapy but show significant donor-to-donor variability and low capacity for the cross-presentation of tumour-associated antigens (TAA) to CD8 þ T cells, greatly limiting the success of this approach. Given recent developments in induced pluripotency and the relative ease with which induced pluripotent stem (iPS) cell lines may be generated from individuals, we have succeeded in differentiating dendritic cells (DC) from human leukocyte antigen (HLA)-A*0201 þ iPS cells (iPS cell-derived DC (ipDC)), using protocols compliant with their subsequent clinical application. Unlike moDC, a subset of ipDC was found to coexpress CD141 and XCR1 that have been shown previously to define the human equivalent of mouse CD8a þ DC, in which the capacity for cross-presentation has been shown to reside. Accordingly, ipDC were able to cross-present the TAA, Melan A, to a CD8 þ T-cell clone and stimulate primary Melan A-specific responses among naïve T cells from an HLA-A*0201 þ donor. Given that CD141 þ XCR1 þ DC are present in peripheral blood in trace numbers that preclude their clinical application, the ability to generate a potentially unlimited source from iPS cells offers the possibility of harnessing their capacity for cross-priming of cytotoxic T lymphocytes for the induction of tumourspecific immune responses.

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Section: Differentiation Of Clinical-grade DC From Human Ips Cellsmentioning

confidence: 99%

Cross-presentation of tumour antigens by human induced pluripotent stem cell-derived CD141+XCR1+ dendritic cells

Silk

Ichiryu

et al. 2011

Gene Ther

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“…Briefly, bone marrow-derived dendritic cells (BMDC) were generated, as previously described (28). Bone marrow cells, obtained from C57BL/6 mouse femora, were resuspended in RPMI 1640 medium supplemented with 10% FCS, 2 mM L-glutamine, 10 mM HEPES, 50 mg/ml gentamicin, and 50 mM 2-ME (all from Invitrogen Life Technologies).…”

Section: In Vitro Production Of Bone Marrow-derived Dendritic Cellsmentioning

confidence: 99%

Negative Regulation of NKG2D Expression by IL-4 in Memory CD8 T Cells

Ventre

Brinza

Schicklin

et al. 2012

The Journal of Immunology

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IL-4 is one of the main cytokines produced during Th2-inducing pathologies. This cytokine has been shown to affect a number of immune processes such as Th differentiation and innate immune responses. However, the impact of IL-4 on CD8 T cell responses remains unclear. In this study, we analyzed the effects of IL-4 on global gene expression profiles of Ag-induced memory CD8 T cells in the mouse. Gene ontology analysis of this signature revealed that IL-4 regulated most importantly genes associated with immune responses. Moreover, this IL-4 signature overlapped with the set of genes preferentially expressed by memory CD8 T cells over naive CD8 T cells. In particular, IL-4 downregulated in vitro and in vivo in a STAT6-dependent manner the memory-specific expression of NKG2D, thereby increasing the activation threshold of memory CD8 T cells. Furthermore, IL-4 impaired activation of memory cells as well as their differentiation into effector cells. This phenomenon could have an important clinical relevance as patients affected by Th2 pathologies such as parasitic infections or atopic dermatitis often suffer from viral-induced complications possibly linked to inefficient CD8 T cell responses.

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“…Efficient cross-presentation is mediated by either prolonged residence of the Ag in the early endosome or decreased degradation in the late endosome (11)(12)(13). Dendritic cell (DC) cross-priming of the TLRmediated CTL response during microbial infection may not only upregulate costimulatory molecules but also regulate this process of cross-presentation (14)(15)(16)(17). However, the molecular mechanisms of TLR-mediated cross-presentation remain unclear.…”

mentioning

confidence: 99%

Molecular Mechanisms of TLR2-Mediated Antigen Cross-Presentation in Dendritic Cells

Shen

Song

Chen

et al. 2014

The Journal of Immunology

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Cross-presentation is a key function of dendritic cells (DCs), which present exogenous Ags on MHC class I molecules to prime CTL responses. The effects of TLR triggering on the cross-presentation of exogenous Ags by DCs remain unclear. In this study, we used synthetic dipalmitoylated peptides and TLR2 agonist–conjugated peptides as models to elucidate the mechanisms of TLR2-mediated cross-presentation. We observed that the internalization of dipalmitoylated peptides by bone marrow–derived DCs was facilitated by TLR2 via clathrin-mediated endocytosis. The administration of these dipalmitoylated peptide-pulsed bone marrow–derived DCs eliminated established tumors through TLR2 signaling. We further demonstrated that the induction of Ag-specific CTL responses and tumor regression by dipalmitoylated peptides was TAP independent. In addition, presentation of dipalmitoylated peptides by MHC class I molecules was blocked in the presence of an endosomal acidification inhibitor (chloroquine) or a lysosomal degradation inhibitor (Z-FL-COCHO). The endocytosed dipalmitoylated peptide also passed rapidly from early endosome Ag-1–positive endosomes to RAS-related GTP-binding protein 7 (Rab7)–associated late endosomes compared with their nonlipidated counterparts. Furthermore, we found that dipalmitoylated peptide–upregulated Rab7 expression correlated with Ag presentation via the TLR2/MyD88 pathway. Both JNK and ERK signaling pathways are required for upregulation of Rab7. In summary, our data suggest that TLR2-mediated cross-presentation occurs through the upregulation of Rab7 and a TAP-independent pathway that prime CTL responses.

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CpG Promotes Cross-Presentation of Dead Cell-Associated Antigens by Pre-CD8α+ Dendritic Cells

Cited by 48 publications

References 52 publications

Cross-presentation of tumour antigens by human induced pluripotent stem cell-derived CD141+XCR1+ dendritic cells

Cross-presentation of tumour antigens by human induced pluripotent stem cell-derived CD141+XCR1+ dendritic cells

Negative Regulation of NKG2D Expression by IL-4 in Memory CD8 T Cells

Molecular Mechanisms of TLR2-Mediated Antigen Cross-Presentation in Dendritic Cells

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