Chapter 12 Structure–Function Dissection of D6, an Atypical Scavenger Receptor

Nibbs, Robert J. B.; McLean, Pauline; McCulloch, Clare V.; Riboldi-Tunnicliffe, A.; Blair, Emma; Zhu, Yan; Isaacs, Neil W.; Graham, Gerard J.

doi:10.1016/s0076-6879(09)05212-4

Cited by 10 publications

(10 citation statements)

References 21 publications

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“…1). This is consistent with continual scavenging of inflammatory CC chemokines (44) by D6 on afferent and subcapsular LECs, which results in intracellular degradation and reduction in the inflammatory chemokines entering the LNs under homeostatic conditions (45). Together with the data presented in this article, we conclude that LECs constitutively scavenge molecules to sample the peripheral lymph entering the LNs.…”

Section: Discussionsupporting

confidence: 87%

Steady-State Antigen Scavenging, Cross-Presentation, and CD8+ T Cell Priming: A New Role for Lymphatic Endothelial Cells

Hirosue

Vokali

Raghavan

et al. 2014

The Journal of Immunology

182

189

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Until recently, the known roles of lymphatic endothelial cells (LECs) in immune modulation were limited to directing immune cell trafficking and passively transporting peripheral Ags to lymph nodes. Recent studies demonstrated that LECs can directly suppress dendritic cell maturation and present peripheral tissue and tumor Ags for autoreactive T cell deletion. We asked whether LECs play a constitutive role in T cell deletion under homeostatic conditions. In this study, we demonstrate that murine LECs under noninflamed conditions actively scavenge and cross-present foreign exogenous Ags to cognate CD8+ T cells. This cross-presentation was sensitive to inhibitors of lysosomal acidification and endoplasmic reticulum–golgi transport and was TAP1 dependent. Furthermore, LECs upregulated MHC class I and the PD-1 ligand PD-L1, but not the costimulatory molecules CD40, CD80, or CD86, upon Ag-specific interactions with CD8+ T cells. Finally, Ag-specific CD8+ T cells that were activated by LECs underwent proliferation, with early-generation apoptosis and dysfunctionally activated phenotypes that could not be reversed by exogenous IL-2. These findings help to establish LECs as APCs that are capable of scavenging and cross-presenting exogenous Ags, in turn causing dysfunctional activation of CD8+ T cells under homeostatic conditions. Thus, we suggest that steady-state lymphatic drainage may contribute to peripheral tolerance by delivering self-Ags to lymph node–resident leukocytes, as well as by providing constant exposure of draining peripheral Ags to LECs, which maintain tolerogenic cross-presentation of such Ags.

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Section: Discussionsupporting

confidence: 87%

Steady-State Antigen Scavenging, Cross-Presentation, and CD8+ T Cell Priming: A New Role for Lymphatic Endothelial Cells

Hirosue

Vokali

Raghavan

et al. 2014

The Journal of Immunology

182

189

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“…This sequence is considered critical for functional coupling of GPCRs to G i -proteins [8], [30]. Restoration of the motif in the scavenger D6 confers weak ligand-induced signaling activity [31]. The expression of all receptors on the cell surface was confirmed by FACS analysis (Figure 2A).…”

Section: Resultsmentioning

confidence: 92%

CXCR7 Functions as a Scavenger for CXCL12 and CXCL11

Naumann¹,

Cameroni²,

et al. 2010

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BackgroundCXCR7 (RDC1), the recently discovered second receptor for CXCL12, is phylogenetically closely related to chemokine receptors, but fails to couple to G-proteins and to induce typical chemokine receptor mediated cellular responses. The function of CXCR7 is controversial. Some studies suggest a signaling activity in mammalian cells and zebrafish embryos, while others indicate a decoy activity in fish. Here we investigated the two propositions in human tissues.Methodology/Principal FindingsWe provide evidence and mechanistic insight that CXCR7 acts as specific scavenger for CXCL12 and CXCL11 mediating effective ligand internalization and targeting of the chemokine cargo for degradation. Consistently, CXCR7 continuously cycles between the plasma membrane and intracellular compartments in the absence and presence of ligand, both in mammalian cells and in zebrafish. In accordance with the proposed activity as a scavenger receptor CXCR7-dependent chemokine degradation does not become saturated with increasing ligand concentrations. Active CXCL12 sequestration by CXCR7 is demonstrated in adult mouse heart valves and human umbilical vein endothelium.Conclusions/SignificanceThe finding that CXCR7 specifically scavenges CXCL12 suggests a critical function of the receptor in modulating the activity of the ubiquitously expressed CXCR4 in development and tumor formation. Scavenger activity of CXCR7 might also be important for the fine tuning of the mobility of hematopoietic cells in the bone marrow and lymphoid organs.

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“…D6 is an atypical chemokine receptor that binds promiscuously to inflammatory chemokines, internalizes them, and directs them for lysosomal degradation without transmitting intracellular signaling events that characterize chemokine receptors (reviewed in refs. 28, 29). Thus, it is considered to be an instrumental cog in the resolution of inflammation.…”

mentioning

confidence: 99%

The atypical chemokine receptor D6 controls macrophage efferocytosis and cytokine secretion during the resolution of inflammation

et al. 2012

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The resolution of acute inflammation is hallmarked by the apoptotic death of inflammatory polymorphonuclear (PMN) cells, followed by their clearance by macrophages. In turn, resolution-phase macrophages exert reduced proinflammatory cytokine production, termed immune silencing. In this study, we found that the atypical chemokine receptor D6 plays an important and chemokine scavenging-independent role in promoting macrophage-mediated resolution. D6(-/-) mice displayed increased numbers of macrophages (2.2-fold increase), but not neutrophils, in their peritonea during the resolution of murine zymosan A-initiated peritonitis, in comparison to D6(+/+) animals. Moreover, D6-deficient macrophages engulfed higher numbers of apoptotic PMN cells in vivo (1.6-fold increase), and secreted higher amounts of TNF-α, CCL3, and CCL5 ex vivo than their wild-type (WT) counterparts. In addition, D6 was found to be expressed on apoptotic neutrophils from healthy humans and rodents. Moreover, the immune silencing of LPS-stimulated macrophages following their incubation with senescent PMN cells ex vivo (in terms of TNF-α, IL-1β, and CCL5 secretion) was diminished (50-65% decrease) when D6(-/-) PMN cells were applied. Accordingly, the adhesive responses induced by macrophage interactions with senescent PMN cells were reduced with D6-deficient PMN cells. Thus, our results indicate a novel mode of action for D6 during the resolution of inflammation that is instrumental to the shaping of resolving macrophage phenotypes and the completion of resolution.

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Chapter 12 Structure–Function Dissection of D6, an Atypical Scavenger Receptor

Cited by 10 publications

References 21 publications

Steady-State Antigen Scavenging, Cross-Presentation, and CD8+ T Cell Priming: A New Role for Lymphatic Endothelial Cells

Steady-State Antigen Scavenging, Cross-Presentation, and CD8+ T Cell Priming: A New Role for Lymphatic Endothelial Cells

CXCR7 Functions as a Scavenger for CXCL12 and CXCL11

The atypical chemokine receptor D6 controls macrophage efferocytosis and cytokine secretion during the resolution of inflammation

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