Steady-state cross-presentation of OVA is mannose receptor-dependent but inhibitable by collagen fragments

Burgdorf, Sven; Schuette, Verena; Semmling, Verena; Hochheiser, Katharina; Lukacs‐Kornek, Veronika; Knolle, Percy A.; Kurts, Christian

doi:10.1073/pnas.1000598107

Cited by 28 publications

(29 citation statements)

References 5 publications

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“…5B). It has been suggested that collagenase digestion routinely used to isolate DCs from tissues may not be compatible with MR detection [22]; however, in our hands, both DC populations were also MR-negative when prepared without collagenase digestion (data not shown). Antigen endocytosed via CD205 (also known as DEC-205) enters the MHC class I and MHC class II antigen presentation pathways and is subsequently presented to both CD8 1 and CD4 1 T cells with high efficiency [23].…”

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confidence: 38%

Thymic but not splenic CD8⁺ DCs can efficiently cross‐prime T cells in the absence of licensing factors

et al. 2011

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Cross-presentation is an important mechanism to elicit both immune defenses and tolerance. Although only a few DC subsets possess the machinery required for crosspresentation, little is known about differences in cross-presenting capabilities of DCs belonging to the same subpopulation but localized in different lymphoid organs. In this study, we demonstrate that steady-state thymic CD81 DCs can efficiently cross-prime naïve CD8 1 T cells in the absence of costimulation. Surprisingly, cross-priming by splenic CD8 1 DCs was dependent on licensing factors such as GM-CSF. In the absence of GM-CSF,antigen-MHC-class-I complexes were detected on thymic but not on splenic CD8 1 DCs, indicating that the cross-presentation capacity of the thymic subpopulation was higher. The observed cross-priming differences between thymic and splenic CD8 1 DCs did not correlate with differential antigen capture or costimulatory molecules found on the surface of DCs. Moreover, we did not detect overall impairment of antigen presentation, as peptide-loaded splenic CD8 1 DCs were able to induce CD8 1 T-cell proliferation. The observation that thymic CD8 1 DCs are more efficient than splenic CD8 1 DCs in T-cell cross-priming in the absence of licensing factors indicates that the requirements for efficient antigen presentation differ between these cells.

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confidence: 38%

Thymic but not splenic CD8⁺ DCs can efficiently cross‐prime T cells in the absence of licensing factors

et al. 2011

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“…In a previous study, we reported the isolation of MR-expressing CD11c + splenocytes that were able to cross-present MR-internalized antigens (26). In contrast, work from other groups pointed out that CD8 + DCs, which are the physiologically relevant cross-presenting cells of the spleen under homeostatic conditions, did not express the MR (27).…”

Section: Resultsmentioning

confidence: 92%

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

Schuette

Embgenbroich

Ulas

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The mannose receptor (MR) is an endocytic receptor involved in serum homeostasis and antigen presentation. Here, we identify the MR as a direct regulator of CD8 + T-cell activity. We demonstrate that MR expression on dendritic cells (DCs) impaired T-cell cytotoxicity in vitro and in vivo. This regulatory effect of the MR was mediated by a direct interaction with CD45 on the T cell, inhibiting its phosphatase activity, which resulted in up-regulation of cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) and the induction of T-cell tolerance. Inhibition of CD45 prevented expression of B-cell lymphoma 6 (Bcl-6), a transcriptional inhibitor that directly bound the CTLA-4 promoter and regulated its activity. These data demonstrate that endocytic receptors expressed on DCs contribute to the regulation of T-cell functionality.T he mannose receptor (MR) is an endocytic receptor belonging to the C-type lectin family and is expressed by distinct populations of dendritic cells (DCs), macrophages, and endothelial cells (1). It consists of an N-terminal cysteine-rich domain (CR), a fibronectin type II (FN II) domain, eight C-type lectinlike domains (CTLDs), a transmembrane region, and a short intracellular region. The CTLDs of the MR can bind to glycoconjugates terminated in mannose, fucose, or glucose. Despite the presence of eight CTLDs, only CTLD4 is responsible for carbohydrate binding. Additionally, the MR can bind to sulfated carbohydrates via its CR and to collagen via its FN II domain (1).In a previous study, we demonstrated that antigens internalized by the MR are processed specifically for cross-presentation (2). The correlation between the MR and cross-presentation offered the possibility that antigens targeted toward the MR could induce potent cytotoxic T-cell responses. Because the induction of a strong cytotoxic T-cell response against tumor-specific antigens is a crucial process in many tumor vaccination strategies, antigen targeting toward the MR seemed to be a promising approach. However, in in vivo tumor models, antigen targeting toward the MR did not result in a strong cytotoxic T-cell response but, instead, led to the induction of antigen-specific T-cell tolerance (3, 4). Therefore, we analyzed whether the MR has a regulatory effect on the induction of immune responses by means distinct from antigen uptake and presentation, and we investigated a direct influence of the MR on T-cell activation. We could demonstrate that the presence of the MR on the antigen-presenting cell (APC) directly impairs the cytotoxic activity of T cells in vitro and in vivo. We showed that this effect was due to a direct interaction of the MR with CD45 on the T-cell surface. This interaction inhibited CD45 activity and resulted in the up-regulation of the inhibitory molecule cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4), which was responsible for the impaired cytotoxic activity of the T cells. ResultsThe Presence of the MR on DCs Reduces Cytotoxic Activity of CD8 + T Cells. To investigate whether the MR influences T-cell ...

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“…49 Hence, to test whether IRAP influences MMR functionality, the kinetics of DQ-OVA uptake and degradation by wt versus IRAP -/-macrophages was assessed using flow cytometry. However, no differences between both macrophage types could be observed (Figure 9).…”

Section: Irap-deficiency Does Not Alter Macrophage Mannose Receptor (mentioning

confidence: 99%

Presence and regulation of insulin-regulated aminopeptidase in mouse macrophages

Nikolaou

Stijlemans

Laoui

et al. 2014

J Renin Angiotensin Aldosterone Syst

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Introduction: The insulin-regulated aminopeptidase (IRAP) is expressed in several cell types, where it is mainly located in specialized secretory endosomes that are quickly recruited to the cell surface upon cell type-specific activation. Here we describe for the first time the expression and subcellular distribution of IRAP in macrophages. Methods: IRAP mRNA expression, protein expression and presence at the cell surface was investigated by real-time polymerase chain reaction (PCR), Western blot and [³H]IVDE77 binding, respectively. Results: IRAP mRNA expression was increased by interferon-γ (IFN-γ) and lipopolysaccharide (LPS), but not by antiinflammatory cytokines (interleukin (IL)-4, IL-10, transforming growth factor β (TGF-β)). IFN-γ increased [³H]IVDE77 binding steadily over time, while LPS quickly and transiently recruited IRAP to the cell surface. Combined stimulations with IFN-γ and LPS showed the same pattern as LPS alone. Latex particles also induced a transient recruitment of IRAP to the cell surface, but no difference was observed in phagocytic uptake between wild-type and IRAP -/-macrophages, suggesting that the enzymatic activity of IRAP is not required for the ingestion of particles. Conclusion: IRAP is more highly expressed in pro-inflammatory M1-activated macrophages and its presence at the cell surface is modulated upon exposure to IFN-γ, LPS or exogenous particles.

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Steady-state cross-presentation of OVA is mannose receptor-dependent but inhibitable by collagen fragments

Cited by 28 publications

References 5 publications

Thymic but not splenic CD8⁺ DCs can efficiently cross‐prime T cells in the absence of licensing factors

Thymic but not splenic CD8⁺ DCs can efficiently cross‐prime T cells in the absence of licensing factors

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

Presence and regulation of insulin-regulated aminopeptidase in mouse macrophages

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Steady-state cross-presentation of OVA is mannose receptor-dependent but inhibitable by collagen fragments

Cited by 28 publications

References 5 publications

Thymic but not splenic CD8+ DCs can efficiently cross‐prime T cells in the absence of licensing factors

Thymic but not splenic CD8+ DCs can efficiently cross‐prime T cells in the absence of licensing factors

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

Presence and regulation of insulin-regulated aminopeptidase in mouse macrophages

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Thymic but not splenic CD8⁺ DCs can efficiently cross‐prime T cells in the absence of licensing factors

Thymic but not splenic CD8⁺ DCs can efficiently cross‐prime T cells in the absence of licensing factors