Membrane‐bound form of fractalkine induces IFN‐γ production by NK cells

Yoneda, Osamu; Imai, Toshio; Nishimura, Miyuki; Miyaji, Michihiko; Mimori, Tsuneyo; Okazaki, Toshiro; Domae, Naochika; Fujimoto, Hiroko; Minami, Yasuhiro; Kono, Toru; Bloom, Eda T.; Umehara, Hisanori

doi:10.1002/immu.200390007

Cited by 53 publications

(41 citation statements)

References 40 publications

(45 reference statements)

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“…Our study implies that CX3CR1 behaves differently when addressing soluble or membrane ligand. A similar difference was recently observed for IFN␥ production by NK cells (41). Our work also shows that the specific mechanism triggered by CX3CR1-IM binding to membrane CX3CL1 is dependent on the PTX-sensitive G-protein family G i (Fig.…”

Section: Discussionsupporting

confidence: 89%

Enhanced Adhesive Capacities of the Naturally Occurring Ile249–Met280 Variant of the Chemokine Receptor CX3CR1

Daoudi

Lavergne

Garin

et al. 2004

Journal of Biological Chemistry

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. We report here that peripheral blood mononuclear cells (PBMC) from individuals with the CX3CR1-IM haplotype adhered more potently to membrane-bound CX3CL1 than did PBMC from homozygous CX3CR1-VT donors. Similar excess adhesion was observed with CX3CR1-IMtransfected human embryonic kidney (HEK) cell lines tested with two different methods: the parallel plate laminar flow chamber and the dual pipette aspiration technique. Suppression of the extra adhesion in the presence of pertussis toxin indicates that G-protein mediated the underlying transduction pathway, in contrast to the G-protein-independent adhesion previously described for CX3CR1-VT. Surprisingly, HEK and PBMC that expressed CX3CR1-IM and -VT were indistinguishable when tested with the soluble form of CX3CL1 for chemotaxis, calcium release, and binding capacity. In conclusion, only the membrane-anchored form of CX3CL1 functionally discriminated between these two allelic isoforms of CX3CR1. These results suggest that each form of this ligand may lead to a different signaling pathway. The extra adhesion of CX3CR1-IM may be related to immune defenses and to atherogenesis, both of which depend substantially on adhesive intercellular events.Adhesion, a critical stage in cell trafficking and migration (1, 2), requires the presence of numerous adhesion molecules, such as integrins, that need divalent ions to function. Recent studies show that two chemokines, namely, CX3CL1 and CXCL16, are not only chemoattractant as soluble molecules, but also function as adhesion molecules since they are membrane-anchored, regardless of the presence of divalent ions (3-7). The best known of these is CX3CL1, also called fractalkine. It is expressed on the surface of many types of cells, in particular interleukin-1-and tumor necrosis factor-activated endothelial (4) and dendritic cells (8), as a membrane molecule containing the classic chemokine domain, a mucin-like stalk, and a transmembrane domain tethering it to the cell membrane. CX3CL1 may be cleaved by TACE and released from cells (9, 10). In this soluble form, it behaves like a chemoattractant molecule, just as other chemokines do. The transmembrane feature of the native CX3CL1 protein, combining it with its receptor, CX3CR1, produces a strongly adhesive pair (4, 5, 11) that mediates the rapid capture and firm adhesion of leukocytes. Because this activity persists in the absence of divalent cations, it is thought to be independent of integrins (5,11,12). This adhesive feature is also independent of the G i pathway, since it is still present after pertussis toxin (PTX) 1 treatment (4, 5, 11). The CX3CR1 molecule is expressed on leukocytes, especially monocytes (4) and cytotoxic cells (13,14), on dendritic cells (15), and on neurons and microglial cells (16,17). Recently, we identified two common polymorphisms in strong linkage disequilibrium in the CX3CR1 gene: V249I and T280M (18). We also found that these mutations are associated with more rapid progression to AIDS (18,19), although two studies have failed to confirm t...

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Section: Discussionsupporting

confidence: 89%

Enhanced Adhesive Capacities of the Naturally Occurring Ile249–Met280 Variant of the Chemokine Receptor CX3CR1

Daoudi

Lavergne

Garin

et al. 2004

Journal of Biological Chemistry

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“…Consistent with a model of chemokine receptor heterodimerization (37), transactivation of growth factor receptor by chemokines has been reported to induce prostate cancer cell invasion (38). Moreover, the membrane-bound form of fractalkine, vehicled by lipid vesicles, was observed to increase natural killer cell activation, compared with the soluble form (39). Due to MV potency as vehicles of selectively sorted biological signals, it is tempting to speculate on their differential effects elicited in target cells possibly resulting from receptor cooperation.…”

Section: Discussionsupporting

confidence: 66%

Membrane Microvesicles as Actors in the Establishment of a Favorable Prostatic Tumoral Niche: A Role for Activated Fibroblasts and CX3CL1-CX3CR1 Axis

et al. 2009

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Tumor microenvironment is enriched in plasma membrane microvesicles (MV) shed from all cell types that constitute the tumor mass, reflecting the antigenic profile of the cells they originate from. Fibroblasts and tumor cells mutually communicate within tumor microenvironment. Recent evidences suggest that tumor-derived MVs (TMV) exert a broad array of biological functions in cell-to-cell communication. To elucidate their role in cancer-to-fibroblast cell communication, TMV obtained from two prostate carcinoma cell lines with high and weak metastatic potential (PC3 and LnCaP, respectively) have been characterized. TMV exhibit matrix metalloproteinases (MMP) and extracellular MMP inducer at their surface, suggesting a role in extracellular matrix degradation. Moreover, TMV not only induce the activation of fibroblasts assessed through extracellular signal-regulated kinase 1/2 phosphorylation and MMP-9 up-regulation, increase motility and resistance to apoptosis but also promote MV shedding from activated fibroblasts able in turn to increase migration and invasion of highly metastatic PC3 cells but not LnCaP cells. PC3 cell chemotaxis seems, at least partially, dependent on membrane-bound CX3CL1/fractalkine ligand for chemokine receptor CX3CR1. The present results highlight a mechanism of mutual communication attributable not only to soluble factors but also to determinants harbored by MV, possibly contributing to the constitution of a favorable niche for cancer development. [Cancer Res 2009;69(3):785-93]

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“…Third, FKN was described to induce a T H 1 amplification circuit: FKN mRNA and protein expression is induced by IL-1, TNF-a, and IFN-g, but not by IL-4 and IL-13, in human endothelial cells (11). In turn, soluble and membrane-bound FKN induce T H 1, but not T H 2, cytokine release from endothelial (12) and NK cells (13). Based on these considerations, the presence of FKN in the neuroblastoma microenvironment should provide for a T H 1 milieu and favor the efficacy of immunotherapy in this disease.…”

Section: Introductionmentioning

confidence: 99%

Fractalkine (CX3CL1)– and Interleukin-2–Enriched Neuroblastoma Microenvironment Induces Eradication of Metastases Mediated by T Cells and Natural Killer Cells

et al. 2007

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Fractalkine (FKN) is a unique CX3C chemokine (CX3CL1) known to induce both adhesion and migration of leukocytes mediated by a membrane-bound and a soluble form, respectively. Its function is mediated through CX3C receptor (CX3CR), which is expressed by T H 1 immune cells including T cells and natural killer (NK) cells. FKN was shown to be expressed in >90% of 68 neuroblastoma samples as determined by cDNA microarray analysis. Here, we characterized the effect of FKN in the neuroblastoma microenvironment using a syngeneic model genetically engineered to secrete FKN. We show FKN-mediated migration, adhesion, and IFN-; secretion of immune effector cells, but limited antineuroblastoma activity, in vitro and in vivo. Therefore, we tested the hypothesis that a combined increase of FKN and interleukin-2 (IL-2) in the neuroblastoma microenvironment induces an effective antitumor immune response. For this purpose, IL-2 was targeted to ganglioside GD2, which is highly expressed on neuroblastoma tissue, using an anti-GD2 antibody IL-2 immunocytokine (ch14.18-IL-2). Only mice bearing FKN-and IL-2-enriched neuroblastoma tumors exhibited a reduction in primary tumor growth and a complete eradication of experimental liver metastases. The depletion of T cells and NK cells in vivo abrogated the effect, and these effector cells showed the highest cytolytic activity in vitro. Finally, only the FKN-and IL-2-enriched neuroblastoma microenvironment resulted in T-cell activation and the release of proinflammatory cytokines. In summary, we showed for the first time the immunologic mechanisms by which targeted IL-2 treatment of neuroblastoma with an FKN-rich microenvironment induces an effective antitumor response. [Cancer Res 2007;67(5):2331-8]

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Membrane‐bound form of fractalkine induces IFN‐γ production by NK cells

Cited by 53 publications

References 40 publications

Enhanced Adhesive Capacities of the Naturally Occurring Ile249–Met280 Variant of the Chemokine Receptor CX3CR1

Enhanced Adhesive Capacities of the Naturally Occurring Ile249–Met280 Variant of the Chemokine Receptor CX3CR1

Membrane Microvesicles as Actors in the Establishment of a Favorable Prostatic Tumoral Niche: A Role for Activated Fibroblasts and CX3CL1-CX3CR1 Axis

Fractalkine (CX3CL1)– and Interleukin-2–Enriched Neuroblastoma Microenvironment Induces Eradication of Metastases Mediated by T Cells and Natural Killer Cells

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