TNFRSF9
Available structures PDB Ortholog search:PDBeRCSB List of PDB id codes 1D0J
Identifiers
Aliases	TNFRSF9, 4-1BB, CD137, CDw137, ILA, tumor necrosis factor receptor superfamily member 9, TNF receptor superfamily member 9
External IDs	OMIM:602250;MGI:1101059;HomoloGene:1199;GeneCards:TNFRSF9;OMA:TNFRSF9 - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p36.23 Start 7,915,871bp[1] End 7,943,165bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4 E2|4 81.52 cM Start 150,999,019bp[2] End 151,030,559bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in buccal mucosa cell lymph node cartilage tissue testicle blood appendix white blood cell monocyte granulocyte gallbladder Top expressed in decidua gastrula blastocyst thymus lymph node mesenteric lymph nodes islet of Langerhans uterus morula blood More reference expression data BioGPS More reference expression data
Gene ontology Molecular function cytokine binding tumor necrosis factor-activated receptor activity signaling receptor activity Cellular component integral component of membrane integral component of plasma membrane membrane external side of plasma membrane extracellular space plasma membrane Biological process multicellular organism development regulation of apoptotic process response to lipopolysaccharide inflammatory response immune response protein homotrimerization apoptotic process negative regulation of cell population proliferation tumor necrosis factor-mediated signaling pathway regulation of cell population proliferation apoptotic signaling pathway Sources:Amigo /QuickGO
Orthologs Species Human Mouse Entrez 3604 21942 Ensembl ENSG00000049249 ENSMUSG00000028965 UniProt Q07011 P20334 RefSeq (mRNA) NM_001561 NM_001077508 NM_001077509 NM_011612 RefSeq (protein) NP_001552 NP_001070976 NP_001070977 NP_035742 Location (UCSC) Chr 1: 7.92 – 7.94 Mb Chr 4: 151 – 151.03 Mb PubMed search [3] [4]
Wikidata
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CD137, a member of the tumor necrosis factor (TNF) receptor family, is atype 1 transmembrane protein, expressed on surfaces of leukocytes and non-immune cells.^[5][6] Its alternative names aretumor necrosis factor receptor superfamily member 9 (TNFRSF9),4-1BB, andinduced by lymphocyte activation (ILA). It is of interest to immunologists as a co-stimulatoryimmune checkpoint molecule, and as a potential target incancer immunotherapy.

CD137 is only expressed on the T-cell cell surface after activation. WhenT cells are activated byAntigen Presenting Cells (APCs), CD137 becomes embedded inCD4+ andCD8+ T cells.^[5]

CD137 is a costimulatory molecule functioning to stimulate T cell proliferation,dendritic cell maturation, and promotion ofB cellantibody secretion.^[7] As a T cell co-stimulator, T cell receptor (TCR) and CD28 signaling causes expression of CD137 on T cell membranes. When CD137 then reacts with the CD137 ligand, it leads to CD137 upregulation.^[7] This is a form of self regulation orpositive feedback cycle. When CD137 interacts with its ligand, it leads to T cellcytokine production and T cell proliferation, among other signaling pathway responses.

Other cells that express CD137 include both immune cells (i.e.monocytes,natural killer cells, dendritic cells,follicular dendritic cells (FDCs), andregulatory T cells) and non-immune cells (i.e.chondrocytes,neurons,astrocytes,microglia andendothelial cells).^[7]

CD137 and its ligand both induce signaling cascades upon interaction, a phenomenon known asbidirectional signal transduction. The CD137/ligand complex is also involved in regulation of the immune system. The CD137 ligand is atype-II transmembrane glycoprotein expressed on APCs.^[8] The CD137 ligand is normally expressed at low levels, but can have increased expression in presence ofpathogen associated molecular patterns (PAMPs) or proinflammatory immune responses likeIL-1 secretion.

Cross-linking CD137 and active T cells can not only result in T cell proliferation via increased IL-2 secretion, but surviving cells also contribute to expanding immune system memory and augmenting T cell cytolytic activity.^[8]

Atherosclerosis is a disease, linked toCardiovascular Disease (CVD), and associated with cardiac inflammation, in the form of lesions in the walls of the atrial chambers and other vasculature.^[9] Treatments designed to target the CD137 molecules expressed on immune cell surfaces often lead to T cell proliferation as CD137 stimulation allows for the T cells to continue through the cell cycle. In this way, CD137 is often referred to as animmune checkpoint. This proliferation eventually leads to other immune cell responses and secretion of proinflammatory cytokines which result in exaggerated inflammatory responses that exacerbate atherosclerosis.^[9] Ongoing studies are researching CD137 as a biomarker for atherosclerosis as well as CD137 antagonists as potential therapeutics to reduce the symptoms associated with the condition.

The mechanism connecting CD137 bidirectional signaling to the promotion of atherosclerosis is related to CD137 mediation of epithelial cell damage. When the CD137/CD137L complex interacts with endothelial cells, including those lining vascular structures, it induces the upregulation of molecules that promote inflammation and damage. For instance, increases inadhesion molecules, including vascular adhesion molecule-1 orintracellular adhesion molecule-1, on epithelial cells causes recruitment of immune cells likemacrophages andneutrophils.^[10] When they arrive, these cells initiate proinflammatory responses including cytokine secretion. In chronic cases, this results in excessive inflammation of the epithelial tissue, leading to cell damage and the formation of atherosclerotic inflammatory lesions.^[10]

CD137 has been shown tointeract withTRAF2.^[11][12]

CD137 is also involved in cancer having been found upregulated in cancerous cell lines. CD137/ligand stimulation has been found to lead to stronger anti-tumor responses due to cytotoxic T cell activation and is being examined as a possible anticancer therapy.^[13]

Current cancer immunotherapy treatments usemonoclonal antibodies (mAbs) to target and kill cancer cells. Cancer cells upregulate cell surface CD137, however the reason behind this remains unclear. What is known is the fact that mAbs targeting CD137 are successful in fighting cancer as they can not only mark cancer cells, but they allow for CD8+ T cell activation and increased IFN-gamma secretion as per CD137's function as a costimulatory molecule.^[14] This enables the affected individual's immune system to actively target and kill cancer cells that express CD137 on their cell surfaces. Currently, Utomilumab is the only mAb targeting CD137 on the market.^[15] Urelumab trials were temporarily halted due to risk of liver toxicity. Utomilumab trials resulted in the drug's being cleared for therapeutic use.

Utomilumab (PF-05082566) targets this receptor to stimulate a more intense immune system attack on cancers.^[16] It is a fully human IgG2 monoclonal antibody.^[17] It is in early clinical trials.^[16] As of June 2016^[update], 5 clinical trials are active.^[18]In recent years, there has been a reignited interest in 4-1BB immunotherapy. Currently, there are several anti-4-1BB antibodies and recombinant proteins are in various stages of clinical trial.^[5]

• 4-1BB ligand
• Urelumab

• HumanTNFRSF9 genome location andTNFRSF9 gene details page in theUCSC Genome Browser.

• Genes on human chromosome 1
• Cancer immunotherapy
• Immunology

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• Articles containing potentially dated statements from June 2016
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