Cutting Edge: Expression of Functional CD137 Receptor by Dendritic Cells

Wilcox, Ryan A.; Chapoval, Andrei I.; Gorski, Kevin; Otsuji, Mizuto; Shin, Tahiro; Flies, Dallas B.; Tamada, Koji; Mittler, Robert S.; Tsuchiya, Haruo; Pardoll, Drew M.; Chen, Lieping

doi:10.4049/jimmunol.168.9.4262

Cited by 211 publications

(187 citation statements)

References 44 publications

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“…Although 4-1BB is mainly involved in regulating activated T lymphocyte functions, expression of 4-1BB has been noted on non-T cells such as B cells, monocytes, macrophages, dendritic cells, eosinophils, and neutrophils (Futagawa et al, 2002;Heinisch et al, 2000;Schwarz et al, 1995;Watts et al, 2005;Wilcox et al, 2002;Yoon et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Mouse 4-1BB Expression: Multiple Promoter Usages and a Splice Variant

Kim

Kwon

2011

Molecules and Cells

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The expression of 4-1BB has been known to be dependent on T cell activation. Recent studies have, however, revealed that 4-1BB expression is not restricted to T cells. We sought to determine the molecular basis for the differential gene expression. Here we report the expression pattern of two mouse 4-1BB transcripts, type I and type II. Whereas the type I transcript was specifically expressed on immune organ as previously reported, the type II transcript was ubiquitously expressed in tissues and various cell lines. However, both type I and type II transcript were highly induced on activated T cells. Primer extension assay of the two 4-1BB transcripts suggested that mouse 4-1BB had more than two transcripts. Using luciferase assay we have identified three promoter regions (PI, PII and PIII), which located on upstream region of second exon 1, first exon 1, and exon 2, respectively. In particular, the type I transcript was preferentially induced when naïve T cells are stimulated by anti-CD3 monoclonal antibody (mAb) since NF-κB specifically binds to the putative NF-κB element of PI. We have also shown that a splice variant, in which the transmembrane domain was deleted, could inhibit 4-1BB signaling. The splicing variant was highly induced by TCR stimulation. Our results reveal 4-1BB also has a negative regulation system through soluble 4-1BB produced from a splice variant induced under activation conditions.

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Section: Introductionmentioning

confidence: 99%

Regulation of Mouse 4-1BB Expression: Multiple Promoter Usages and a Splice Variant

Kim

Kwon

2011

Molecules and Cells

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“…In addition, the intracellular signaling pathways downstream of 4-1BB and RANK are very similar [13,14]. Recent studies showed that 4-1BB is expressed on dendritic cells and monocytes as well as on T cells, and modulates the function of these cells [15,16]. Furthermore, reverse signaling through 4-1BBL on monocytes induces the secretion of inflammatory cytokines, monocyte proliferation, and endomitosis [17,18].…”

Section: Introductionmentioning

confidence: 99%

The 4–1BB ligand and 4–1BB expressed on osteoclast precursors enhance RANKL‐induced osteoclastogenesis via bi‐directional signaling

et al. 2008

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The 4-1BB is a costimulatory molecule similar to the receptor activator of NF-jB ligand (RANKL), both of which are key factors for the differentiation of osteoclasts and are expressed mainly by activated T cells. The 4-1BB shares common signaling pathways with RANK, suggesting a potential role in osteoclastogenesis. In this study, the role of 4-1BB and 4-1BB ligand (4-1BBL) in osteoclastogenesis was investigated using 4-1BB -/-and 4-1BB +/+ mice. Osteoclast precursors normally express 4-1BB and 4-1BBL after exposure to RANKL, which was confirmed by semi-quantitative RT-PCR and flow cytometry. The 4-1BB -/-mice had a slightly increased bone mass accompanied by a reduced osteoclastogenic ability of 4-1BB -/-bone marrow-derived macrophages (BMM) ex vivo. In addition, 4-1BB -/-BMM demonstrated hypophosphorylation of JNK and p38 and decreased induction of c-Fos in response to RANKL stimulation. Retroviral transduction of wild-type as well as partiallength 4-1BB, which lacks TNF receptor-associated factor 2-binding sites for signaling, restored the osteoclastogenic ability of 4-1BB -/-BMM. Furthermore, both recombinant 4-1BB and 4-1BBL enhanced RANKL-induced osteoclastogenesis by 4-1BB +/+ BMM and the induction of c-Fos and NFATc1.Together, these results indicate that 4-1BBL and 4-1BB expressed on osteoclast precursors enhance RANKL-induced osteoclastogenesis via bi-directional signaling, findings that may delineate the complex nature of the 4-1BBL and 4-1BB interaction.

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“…1,2 4-1BB is an inducible protein expressed on the surface of activated T lymphocytes, 3 natural killer (NK) cells, 4 and dendritic cells (DCs). [5][6][7] It is a member of the tumor necrosis factor/nerve growth factor family of receptors that includes CD40, CD27, CD30, and OX-40. Its natural ligand, 4-1BB ligand (4-1BBL), is expressed on activated APC, including B cells, macrophages, and DCs.…”

Section: Introductionmentioning

confidence: 99%

“…9 In vivo activation of 4-1BB signaling by the administration of agonistic 4-1BB antibodies or 4-1BB L-transduced tumor cells resulted in the regression of some tumors. 6,[9][10][11] We previously showed that the combination of 4-1BB costimulation by an agonistic antibody with IL-12 gene transfer induced a significant synergistic antitumor response in a mouse colon carcinoma model. In order to minimize the inherent dangers involved with the introduction of foreign antigen, for example, agonistic antibody, to patients in future clinical trials, we further tested the efficacy of an adenovirus (ADV) expressing membrane-bound 4-1BBL (ADV/4-1BBLm), which is the natural ligand for this receptor.…”

Section: Introductionmentioning

confidence: 99%

The systemic administration of Ig-4-1BB ligand in combination with IL-12 gene transfer eradicates hepatic colon carcinoma

et al. 2005

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We have previously shown that the local-membrane bound 4-1BB ligand and IL-12 gene transfer induced a significant antitumor response in a mouse colon carcinoma model. However, a high viral dose was required in order to achieve the best efficacy. In this study, we hypothesize that the systemic administration of soluble Ig-4-1BB ligand can give rise to better T-cell immune activation than local gene delivery. With potential clinical applications in mind, we further compare whether the natural 4-1BB ligand fused to mouse IgG2a (Ig-4-1BBL) would be as effective as the agonistic anti-4-1BB antibody. The dimeric form of Ig-4-1BBL was purified from HeLa cells transduced with a recombinant adenovirus (ADV/ Ig-4-1BBL) expressing Ig-4-1BBL. Functional activity was confirmed by the ligand's ability to bind to activated splenic T cells or bone marrow (BM)-derived dendritic cells (DCs) that express 4-1BB receptor. The soluble Ig-4-1BBL efficiently costimulated CD3-activated T-cell proliferation in vitro. More importantly, it induced tumor-specific CTLs as effectively as the agonistic anti-4-1BB antibody. When combined with IL-12 gene transfer, systemic administration of the Ig-4-1BBL proved to be more potent than local gene delivery. In addition, the Ig-4-1BBL is as potent as the agonistic anti-4-1BB antibody for the treatment of hepatic MCA26 colon carcinoma, resulting in 50% complete tumor regression and long-term survival. In long-term surviving mice, both treatment modalities induced persistent tumor-specific CTL activity. In summary, these results suggest that the systemic delivery of Ig-4-1BBL can generate a better antitumor response than local gene delivery. Ig-4-1BBL had equivalent biological functions when compared to the agonistic anti-4-1BB antibody. Thus, soluble 4-1BBL dimmer can be developed as a promising agent for cancer therapy in humans. Gene Therapy (2005) 12, 1526-1533.

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Cutting Edge: Expression of Functional CD137 Receptor by Dendritic Cells

Cited by 211 publications

References 44 publications

Regulation of Mouse 4-1BB Expression: Multiple Promoter Usages and a Splice Variant

Regulation of Mouse 4-1BB Expression: Multiple Promoter Usages and a Splice Variant

The 4–1BB ligand and 4–1BB expressed on osteoclast precursors enhance RANKL‐induced osteoclastogenesis via bi‐directional signaling

The systemic administration of Ig-4-1BB ligand in combination with IL-12 gene transfer eradicates hepatic colon carcinoma

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