Identification of regulatory functions for 4-1BB and 4-1BBL in myelopoiesis and the development of dendritic cells

Lee, Seung Woo; Park, Yunji; So, Takanori; Kwon, Byoung S.; Cheroutre, Hilde; Mittler, Robert S.; Croft, Michael

doi:10.1038/ni.1632

Cited by 77 publications

(110 citation statements)

References 49 publications

(69 reference statements)

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“…CD137L protein expressed by LPS-induced TLR4 signaling physically interacts with TLR4, and this interaction is required for LPS-induced sustained TNF production in macrophages [32]. Lee et al, reported that CD137L reverse signals inhibit myelopoiesis and the development of DC [33]. On the other hand, others showed that CD137L ligation enhances proliferation of hematopietic progenitor cells and its differentiation to monocytes, macrophages [34,35].…”

Section: Discussionmentioning

confidence: 99%

CD137 ligand‐mediated reverse signals increase cell viability and cytokine expression in murine myeloid cells: Involvement of mTOR/p70S6 kinase and Akt

Kim

Lee

2009

Eur J Immunol

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Cross-linking of CD137 ligand (CD137L), a member of the TNF family, with recombinant CD137-Fc (rCD137-Fc) protein enhanced adherence of bone marrow-derived macrophages, and increased the expression of ICAM-1, IL-1b, IL-6, M-CSF and phosphotyrosine proteins. In RAW264.7 cells, a murine myeloid cell line, rCD137-Fc not only increased adherence but also cell multiplication, in a manner comparable to LPS or M-CSF. In addition, it upregulated expression of IL-1b, IL-1 receptor antagonist, IL-6, COX2, tenascin C, neuropeptide Y and M-CSF mRNA. Neutralization of M-CSF by incubating the RAW264.7 cells with anti-M-CSF mAb did not prevent the CD137L signal-induced viability. Viability was blocked by PP2, an Src tyrosine kinase inhibitor, rapamycin, an mTOR inhibitor and LY294002, a PI3K inhibitor, but not by Wortmannin, another PI3K inhibitor. Cross-linking of CD137L increased phosphorylation of Akt and p70S6 kinase. The latter was blocked by PP2, rapamycin or LY294002, but not by Wortmannin, whereas phosphorylation of Akt was blocked by LY294002 or Wortmannin. These findings demonstrate that reverse signals evoked by CD137L regulate immune functions in macrophages.

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Section: Discussionmentioning

confidence: 99%

CD137 ligand‐mediated reverse signals increase cell viability and cytokine expression in murine myeloid cells: Involvement of mTOR/p70S6 kinase and Akt

Kim

Lee

2009

Eur J Immunol

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“…In addition, antigen-independent anti-CD137 mAb effects have been described for memory T cells, and CD137 seems to be an important player in the differentiation of memory cells [8][9][10]. CD137 can also be expressed by activated NK cells [11], myeloid leukocytes [12] including DC [13,14], and tumor endothelial cells [15]. However, the role of CD137 molecules expressed on these non-T cells during tumor immunotherapy remains undefined [13,16].…”

Section: Introductionmentioning

confidence: 99%

“…CD137 can also be expressed by activated NK cells [11], myeloid leukocytes [12] including DC [13,14], and tumor endothelial cells [15]. However, the role of CD137 molecules expressed on these non-T cells during tumor immunotherapy remains undefined [13,16].…”

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confidence: 99%

In vivo depletion of DC impairs the anti‐tumor effect of agonistic anti‐CD137 mAb

et al. 2009

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Anti-CD137 mAb are capable of inducing tumor rejection in several syngeneic murine tumor models and are undergoing clinical trials for cancer. The anti-tumor effect involves costimulation of tumor-specific CD8 1 T cells. Whether antigen cross-presenting DC are required for the efficacy of anti-CD137 mAb treatment has never been examined. Here we show that the administration of anti-CD137 mAb eradicates EG7-OVA tumors by a strictly CD8b 1 T-celldependent mechanism that correlates with increased CTL activity. Ex vivo analyses to determine the identity of the draining lymph node cell type responsible for tumor antigen crosspresentation revealed that CD11c 1 cells, most likely DC, are the main players in this tumor model. A minute number of tumor cells, revealed by the presence of OVA cDNA, reach tumordraining lymph nodes. Direct antigen presentation by tumor cells themselves also participates in anti-OVA CTL induction. Using CD11c diphtheria toxin receptor-green fluorescent protein-C57BL/6 BM chimeric mice, which allow for sustained ablation of DC with diphtheria toxin, we confirmed the involvement of DC in tumor antigen cross-presentation in CTL induction against OVA [257][258][259][260][261][262][263][264] epitope and in the antitumor efficacy induced by anti-CD137 mAb.Key words: CD137 (4-1BB) . Cross-priming . CTL . DC . Tumor immunity Supporting Information available online Introduction CD137, also known as 4-1BB, is a TNF-receptor family costimulatory molecule originally identified on activated T cells [1]. Its natural ligand CD137L is found on APC, including B cells, macrophages, and DC [2]. In the presence of TCR engagement, signaling through CD137 leads to increased T-cell proliferation, cytokine production, and prolonged CD8 1 T-cell survival in vitro [2]. Administration of agonistic anti-CD137 mAb either alone or following peptide vaccination is capable of inducing the eradication of established tumors in several transplantable tumor models [3,4]. This anti-tumor effect is dependent on CD8 1 T cells that show increases in tumor-specific cytotoxic activity and associated IFN-g production [3,4]. Recent studies have demonstrated that the activity of anti-CD137 mAb treatment is also dependent on their ability to enhance the survival of CD8 1 CTL, and on the prevention/reversal of established anergy [5][6][7]. In addition, antigen-independent anti-CD137 mAb effects have been described for memory T cells, and CD137 seems to be an Ã These authors contributed equally to this work.ÃÃ These authors share equal senior authorship. 2424important player in the differentiation of memory cells [8][9][10]. CD137 can also be expressed by activated NK cells [11], myeloid leukocytes [12] including DC [13,14], and tumor endothelial cells [15]. However, the role of CD137 molecules expressed on these non-T cells during tumor immunotherapy remains undefined [13,16].As naïve CTL do not express CD137 on their surface, susceptibility to CD137 triggering depends on prior up-regulation of this receptor [5]. This requires antigen rec...

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“…Several TNF family members expressed by APCs can costimulate T cell activation by binding to specific TNFR family members expressed on T cells. 4-1BB (CD137) ligand and OX40 (CD134) ligand, two costimulatory receptors of the TNF family, are expressed on APCs and their ligandreceptor pairs could provide costimulatory signals from APCs to T cells (3). CD27 and CD30 are two additional TNFR family members expressed by T cells that might be interesting targets for the activation or inhibition of antigenspecific responses.…”

Section: Introductionmentioning

confidence: 99%

Intracellular Signals of T Cell Costimulation

et al. 2008

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Identification of regulatory functions for 4-1BB and 4-1BBL in myelopoiesis and the development of dendritic cells

Cited by 77 publications

References 49 publications

CD137 ligand‐mediated reverse signals increase cell viability and cytokine expression in murine myeloid cells: Involvement of mTOR/p70S6 kinase and Akt

CD137 ligand‐mediated reverse signals increase cell viability and cytokine expression in murine myeloid cells: Involvement of mTOR/p70S6 kinase and Akt

In vivo depletion of DC impairs the anti‐tumor effect of agonistic anti‐CD137 mAb

Intracellular Signals of T Cell Costimulation

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