scholarly journals The C-type lectin receptor CLEC9A mediates antigen uptake and (cross-)presentation by human blood BDCA3+ myeloid dendritic cells

Blood ◽  
2012 ◽  
Vol 119 (10) ◽  
pp. 2284-2292 ◽  
Author(s):  
Gerty Schreibelt ◽  
Lieke J. J. Klinkenberg ◽  
Luis J. Cruz ◽  
Paul J. Tacken ◽  
Jurjen Tel ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mhc Class Ii ◽  
Receptor Internalization ◽  
Cell Surface Expression ◽  
Antigen Delivery ◽  
Myeloid Dendritic Cells ◽  
Antigen Uptake ◽  
Cross Presentation ◽  
Lectin Receptor

Abstract CLEC9A is a recently discovered C-type lectin receptor involved in sensing necrotic cells. In humans, this receptor is selectively expressed by BDCA3+ myeloid dendritic cells (mDCs), which have been proposed to be the main human cross-presenting mDCs and may represent the human homologue of murine CD8+ DCs. In mice, it was demonstrated that antigens delivered with antibodies to CLEC9A are presented by CD8+ DCs to both CD4+ and CD8+ T cells and induce antitumor immunity in a melanoma model. Here we assessed the ability of CLEC9A to mediate antigen presentation by human BDCA3+ mDCs, which represent < 0.05% of peripheral blood leukocytes. We demonstrate that CLEC9A is only expressed on immature BDCA3+ mDCs and that cell surface expression is lost after TLR-mediated maturation. CLEC9A triggering via antibody binding rapidly induces receptor internalization but does not affect TLR-induced cytokine production or expression of costimulatory molecules. More importantly, antigens delivered via CLEC9A antibodies to BDCA3+ mDCs are presented by both MHC class I (cross-presentation) and MHC class II to antigen-specific T cells. We conclude that CLEC9A is a promising target for in vivo antigen delivery in humans to increase the efficiency of vaccines against infectious or malignant diseases.

scholarly journals Glycan modification of antigen alters its intracellular routing in dendritic cells, promoting priming of T cells

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Ingeborg Streng-Ouwehand ◽  
Nataschja I Ho ◽  
Manja Litjens ◽  
Hakan Kalay ◽  
Martine Annemarie Boks ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Glycan Structure ◽  
Antigen Uptake ◽  
Lectin Receptors ◽  
Cross Presentation ◽  
Lectin Receptor ◽  
Intracellular Storage ◽  
Glycan Modification

Antigen uptake by dendritic cells and intracellular routing of antigens to specific compartments is regulated by C-type lectin receptors that recognize glycan structures. We show that the modification of Ovalbumin (OVA) with the glycan-structure LewisX (LeX) re-directs OVA to the C-type lectin receptor MGL1. LeX-modification of OVA favored Th1 skewing of CD4+ T cells and enhanced cross-priming of CD8+ T cells. While cross-presentation of native OVA requires high antigen dose and TLR stimuli, LeX modification reduces the required amount 100-fold and obviates its dependence on TLR signaling. The OVA-LeX-induced enhancement of T cell cross-priming is MGL1-dependent as shown by reduced CD8+ effector T cell frequencies in MGL1-deficient mice. Moreover, MGL1-mediated cross-presentation of OVA-LeX neither required TAP-transporters nor Cathepsin-S and was still observed after prolonged intracellular storage of antigen in Rab11+LAMP1+ compartments. We conclude that controlled neo-glycosylation of antigens can crucially influence intracellular routing of antigens, the nature and strength of immune responses and should be considered for optimizing current vaccination strategies.

scholarly journals Constitutive Presentation of a Natural Tissue Autoantigen Exclusively by Dendritic Cells in the Draining Lymph Node

2002 ◽  
Vol 196 (8) ◽  
pp. 1079-1090 ◽  
Author(s):  
Clemens Scheinecker ◽  
Rebecca McHugh ◽  
Ethan M. Shevach ◽  
Ronald N. Germain
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Lymph Node ◽  
Mhc Class Ii ◽  
Tissue Destruction ◽  
Antigen Uptake ◽  
Autoreactive T Cells ◽  
Gastric Parietal Cell ◽  
Tissue Specific

The major histocompatibility complex (MHC)-dependent presentation of processed tissue-specific self-antigens can contribute to either peripheral (extrathymic) tolerance or the differentiation of autoreactive T cells. Here, we have studied the MHC class II molecule presentation of gastric parietal cell (PC)-specific H+/K+-ATPase, which induces a destructive autoimmune gastritis in BALB/c mice lacking CD4+ CD25+ regulatory T cells. Immunofluorescence microscopy showed physical association of CD11c+ dendritic cells (DCs) with PCs in the gastric mucosa. H+/K+-ATPase protein was found within vesicular compartments of a few CD11c+ DCs only in the draining gastric lymph node (LN) and these antigen-containing DCs increased markedly in number with the onset of tissue destruction in autoimmune animals. Both CD8αhi and CD8αlo gastric DCs, but not peripheral or mesenteric DCs, showed evidence of constitutive in vivo processing and presentation of H+/K+-ATPase. These data provide direct support for a widely held model of local tissue antigen uptake and trafficking by DCs in normal animals and demonstrate that DCs in the draining LN can present a tissue-specific self-antigen under noninflammatory conditions without fully deleting autoreactive T cells or inducing active autoimmunity.

scholarly journals Absence of MHC class II on cDC1 dendritic cells triggers fatal autoimmunity to a cross-presented self-antigen

2020 ◽  
Vol 5 (45) ◽  
pp. eaba1896 ◽  
Author(s):  
Christian Wohn ◽  
Valentin Le Guen ◽  
Odessa Voluzan ◽  
Frédéric Fiore ◽  
Sandrine Henri ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Cross Presentation ◽  
Conditional Deletion ◽  
Autoimmune Condition ◽  
To Receive ◽  
Self Antigen

Conventional dendritic cells expressing the XCR1 chemokine receptor (cDC1s) excel at cross-presentation. Here, we developed and used a mouse model in which a Cre recombinase is expressed under the control of the Xcr1 gene while preserving XCR1 expression. We used it to generate mice with conditional deletion of MHC class II (MHCII) molecules on cDC1s. By preventing cDC1s to receive suppressive regulatory T cell inputs via MHCII-restricted interactions, the objective of the present study was to gauge whether MHCII-deficient cDC1s lose their capacity of tolerizing autoreactive CD8+ T cells. Whereas MHCII+ cDC1 readily cross-tolerized strongly autoreactive CD8+ T cells specific for a keratinocyte-derived self-antigen, MHCII-deficient cDC1s converted them into potent effectors capable of triggering a fast-onset lethal autoimmunity associated with severe skin histopathological manifestations. Preventing egress of such pathogenic self-reactive CD8+ T cell effectors from the cutaneous draining lymph nodes abrogated the autoimmune condition. Therefore, our results revealed that the cross-tolerizing capacity of cDC1s is not a property fully acquired at the time they undergo homeostatic maturation but needs to be enforced via MHCII-restricted, suppressive interactions with regulatory T cells.

scholarly journals Antigen delivery to early endosomes eliminates the superiority of human blood BDCA3+ dendritic cells at cross presentation

2013 ◽  
Vol 210 (5) ◽  
pp. 1049-1063 ◽  
Author(s):  
Lillian Cohn ◽  
Bithi Chatterjee ◽  
Filipp Esselborn ◽  
Anna Smed-Sörensen ◽  
Norihiro Nakamura ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Antigen Delivery ◽  
Cross Presentation ◽  
Late Endosomes ◽  
Early Endosomes ◽  
Intracellular Compartments ◽  
Endocytic Compartments

Human BDCA3+ dendritic cells (DCs), the proposed equivalent to mouse CD8α+ DCs, are widely thought to cross present antigens on MHC class I (MHCI) molecules more efficiently than other DC populations. If true, it is unclear whether this reflects specialization for cross presentation or a generally enhanced ability to present antigens on MHCI. We compared presentation by BDCA3+ DCs with BDCA1+ DCs using a quantitative approach whereby antigens were targeted to distinct intracellular compartments by receptor-mediated internalization. As expected, BDCA3+ DCs were superior at cross presentation of antigens delivered to late endosomes and lysosomes by uptake of anti-DEC205 antibody conjugated to antigen. This difference may reflect a greater efficiency of antigen escape from BDCA3+ DC lysosomes. In contrast, if antigens were delivered to early endosomes through CD40 or CD11c, BDCA1+ DCs were as efficient at cross presentation as BDCA3+ DCs. Because BDCA3+ DCs and BDCA1+ DCs were also equivalent at presenting peptides and endogenously synthesized antigens, BDCA3+ DCs are not likely to possess mechanisms for cross presentation that are specific to this subset. Thus, multiple DC populations may be comparably effective at presenting exogenous antigens to CD8+ T cells as long as the antigen is delivered to early endocytic compartments.

scholarly journals CD1-mediated γ/δ T Cell Maturation of Dendritic Cells

2002 ◽  
Vol 196 (12) ◽  
pp. 1575-1584 ◽  
Author(s):  
David S. Leslie ◽  
Michael S. Vincent ◽  
Franca M. Spada ◽  
Hiranmoy Das ◽  
Masahiko Sugita ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Adaptive Immune Response ◽  
Cell Contact ◽  
Human Immune System ◽  
Myeloid Dendritic Cells ◽  
Microbial Invasion ◽  
Factor Α

Immature myeloid dendritic cells (DCs) express only low levels of major histocompatibility complex (MHC) class II but express high levels of CD1 a, b, and c antigen-presenting molecules at the cell surface. As Vδ1+ γ/δ T cells are the main tissue subset of γ/δ T cells and they are known to recognize CD1c in the absence of specific foreign antigen recognition, we examined the possible interaction of these T cells with immature DCs. We show that CD1-restricted γ/δ T cells can mediate the maturation of DCs. DC maturation required cell–cell contact and could be blocked by antibodies against CD1c. The maturation process was partially mediated by tumor necrosis factor α. Importantly, immature DCs matured in the presence of lipopolysaccharide and CD1-restricted γ/δ T cells produced bioactive interleukin-12p70. In addition, these DCs were able to efficiently present peptide antigens to naive CD4+ T cells. CD1-restricted γ/δ T cell recognition of immature DCs provides the human immune system with the capacity to rapidly generate a pool of mature DCs early during microbial invasion. This may be an important source of critical host signals for T helper type 1 polarization of antigen-specific naive T cells and the subsequent adaptive immune response.

scholarly journals CD1d on Myeloid Dendritic Cells Stimulates Cytokine Secretion from and Cytolytic Activity of Vα24JαQ T Cells: A Feedback Mechanism for Immune Regulation

2000 ◽  
Vol 165 (7) ◽  
pp. 3756-3762 ◽  
Author(s):  
Otto O. Yang ◽  
Frederick K. Racke ◽  
Phuong Thi Nguyen ◽  
Rudolf Gausling ◽  
Michael E. Severino ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Regulation ◽  
Feedback Mechanism ◽  
Cytolytic Activity ◽  
Cytokine Secretion ◽  
Myeloid Dendritic Cells

scholarly journals Distinct antigen uptake receptors route to the same storage compartments for cross‐presentation in dendritic cells

Immunology ◽  
2021 ◽  
Author(s):  
Nataschja I. Ho ◽  
Marcel G. Camps ◽  
Juan J. Garcia‐Vallejo ◽  
Erik Bos ◽  
Abraham J. Koster ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antigen Uptake ◽  
Cross Presentation

scholarly journals Murine Myeloid Dendritic Cells That Phagocytose Apoptotic T Cells Inhibit the Immune Response via NO

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e49378 ◽  
Author(s):  
Kaili Zhong ◽  
Wengang Song ◽  
Qian Wang ◽  
Chao Wang ◽  
Xi Liu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Myeloid Dendritic Cells

scholarly journals Methotrexate enhances antigen presentation and maturation of tumour antigen-loaded dendritic cells through NLRP3 inflammasome activation: a strategy for dendritic cell-based cancer vaccine

2021 ◽  
Vol 13 ◽  
pp. 175883592098705
Author(s):  
Gao-Na Shi ◽  
Min Hu ◽  
Chengjuan Chen ◽  
Junmin Fu ◽  
Shuai Shao ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Nlrp3 Inflammasome ◽  
Tumour Antigen ◽  
Inflammasome Activation ◽  
Antigen Uptake ◽  
Nlrp3 Inflammasome Activation ◽  
Dc Maturation

Background: Dendritic cells (DCs) are antigen-presenting cells that play a pivotal role in adaptive cell-mediated immunity by priming and activating T cells against specific tumour and pathogenic antigens. Methotrexate (MTX), a folate derivative, functions as an immunoregulatory agent. However, the possible effect of MTX on tumour antigen-loaded DCs has not yet been investigated. Methods: We analysed the effect of MTX on the maturation and function of DCs along with tumour cell lysates (TCLs). Using bone marrow-derived DCs, we investigated the effect of MTX combined TCL-loaded DCs on T cells priming and proliferation. We also tested the anti-tumour immune effect on DCs when treated with MTX and/or TCL in vivo. Results: MTX combined with TCL not only enhanced DC maturation and stimulated cytokine release but also promoted CD8+ T cell activation and proliferation. The latter was associated with increased tumour antigen uptake and cross-presentation to T cells. Mechanistically, DC maturation and antigen presentation were partly modulated by NLRP3 inflammasome activation. Furthermore, immunisation of mice with MTX and TCL-pulsed DCs before a tumour challenge significantly delayed tumour onset and retarded its growth. This protective effect was due to priming of IFN-γ releasing CD8+ T cells and enhanced killing of tumour cells by cytotoxic T lymphocytes isolated from these immunised mice. Conclusion: MTX can function as a potent adjuvant in DC vaccines by increasing antigen presentation and T cell priming. Our findings provide a new strategy for the application of DC-based anti-tumour immunotherapy.

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