CD134

TNFRSF4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1D0A, 2HEV, 2HEY
Identifiers
Aliases	TNFRSF4, ACT35, CD134, IMD16, OX40, TXGP1L, tumor necrosis factor receptor superfamily member 4, TNF receptor superfamily member 4
External IDs	OMIM: 600315; MGI: 104512; HomoloGene: 2496; GeneCards: TNFRSF4; OMA:TNFRSF4 - orthologs
Gene location (Human) Chr. Chromosome 1 (human) Band 1p36.33 Start 1,211,340 bp End 1,214,153 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in apex of heart granulocyte gonad spleen lymph node cartilage tissue mucosa of transverse colon upper lobe of left lung blood appendix n/a More reference expression data BioGPS More reference expression data
Gene ontology Molecular function virus receptor activity tumor necrosis factor-activated receptor activity protein binding Cellular component integral component of membrane membrane plasma membrane integral component of plasma membrane cell surface external side of plasma membrane Biological process regulation of apoptotic process tumor necrosis factor-mediated signaling pathway negative regulation of DNA-binding transcription factor activity multicellular organism development T cell proliferation response to lipopolysaccharide regulation of cell population proliferation positive regulation of B cell proliferation immune response apoptotic signaling pathway viral entry into host cell inflammatory response negative regulation of transcription, DNA-templated viral process cellular defense response regulation of protein kinase activity negative regulation of activation-induced cell death of T cells negative regulation of extrinsic apoptotic signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7293 22163 Ensembl ENSG00000186827 n/a UniProt P43489 P47741 RefSeq (mRNA) NM_003327 NM_011659 RefSeq (protein) NP_003318 NP_035789 Location (UCSC) Chr 1: 1.21 – 1.21 Mb n/a PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4), also known as CD134 and OX40 receptor, is a member of the TNFR-superfamily of receptors which is not constitutively expressed on resting naïve T cells, unlike CD28. OX40 is a secondary co-stimulatory immune checkpoint molecule, expressed after 24 to 72 hours following activation; its ligand, OX40L, is also not expressed on resting antigen presenting cells, but is following their activation. Expression of OX40 is dependent on full activation of the T cell; without CD28, expression of OX40 is delayed and of fourfold lower levels.

Function

OX40 has no effect on the proliferative abilities of CD4+ cells for the first three days, however after this time proliferation begins to slow and cells die at a greater rate, due to an inability to maintain a high level of PKB activity and expression of Bcl-2, Bcl-XL and survivin. OX40L binds to OX40 receptors on T-cells, preventing them from dying and subsequently increasing cytokine production. OX40 has a critical role in the maintenance of an immune response beyond the first few days and onwards to a memory response due to its ability to enhance survival. OX40 also plays a crucial role in both Th1 and Th2 mediated reactions in vivo.

OX40 binds TRAF2, 3 and 5 as well as PI3K by an unknown mechanism. TRAF2 is required for survival via NF-κB and memory cell generation whereas TRAF5 seems to have a more negative or modulatory role, as knockouts have higher levels of cytokines and are more susceptible to Th2-mediated inflammation. TRAF3 may play a critical role in OX40-mediated signal transduction. CTLA-4 is down-regulated following OX40 engagement in vivo and the OX40-specific TRAF3 DN defect was partially overcome by CTLA-4 blockade in vivo. TRAF3 may be linked to OX40-mediated memory T cell expansion and survival, and point to the down-regulation of CTLA-4 as a possible control element to enhance early T cell expansion through OX40 signaling.

Clinical significance

OX40 has been implicated in the pathologic cytokine storm associated with certain viral infections, including the H5N1 bird flu.

As a drug or drug target

An artificially created biologic fusion protein, OX40-immunoglobulin (OX40-Ig), prevents OX40 from reaching the T-cell receptors, thus reducing the T-cell response. Experiments in mice have demonstrated that OX40-Ig can reduce the symptoms associated with the cytokine storm (an immune overreaction) while allowing the immune system to fight off the virus successfully.

An anti-OX40 antibody GSK3174998 has started clinical trials as a cancer treatment. Research in mice has included the combination of an agonistic OX40 antibody (clone OX86) injected directly into a tumor in combination with an unmethylated CpG oligonucleotide, which as a TLR9 ligand activates expression of OX40 so that it can be affected.

Interactions

CD134 has been shown to interact with TRAF5 and TRAF2.

External links

• Human TNFRSF4 genome location and TNFRSF4 gene details page in the UCSC Genome Browser.

Further reading

• So T, Salek-Ardakani S, Nakano H, Ware CF, Croft M (April 2004). "TNF receptor-associated factor 5 limits the induction of Th2 immune responses". Journal of Immunology. 172 (7): 4292–7. doi:10.4049/jimmunol.172.7.4292. PMID 15034043.4292-7&rft.date=2004-04&rft_id=info:doi/10.4049/jimmunol.172.7.4292&rft_id=info:pmid/15034043&rft.aulast=So&rft.aufirst=T&rft.au=Salek-Ardakani,+S&rft.au=Nakano,+H&rft.au=Ware,+CF&rft.au=Croft,+M&rft_id=https://doi.org/10.4049%2Fjimmunol.172.7.4292&rfr_id=info:sid/en.wikipedia.org:CD134" class="Z3988">
• Song J, Salek-Ardakani S, Rogers PR, Cheng M, Van Parijs L, Croft M (February 2004). "The costimulation-regulated duration of PKB activation controls T cell longevity". Nature Immunology. 5 (2): 150–8. doi:10.1038/ni1030. PMID 14730361. S2CID 10102422.150-8&rft.date=2004-02&rft_id=https://api.semanticscholar.org/CorpusID:10102422#id-name=S2CID&rft_id=info:pmid/14730361&rft_id=info:doi/10.1038/ni1030&rft.aulast=Song&rft.aufirst=J&rft.au=Salek-Ardakani,+S&rft.au=Rogers,+PR&rft.au=Cheng,+M&rft.au=Van+Parijs,+L&rft.au=Croft,+M&rfr_id=info:sid/en.wikipedia.org:CD134" class="Z3988">
• Song J, So T, Cheng M, Tang X, Croft M (May 2005). "Sustained survivin expression from OX40 costimulatory signals drives T cell clonal expansion". Immunity. 22 (5): 621–31. doi:10.1016/j.immuni.2005.03.012. PMID 15894279.621-31&rft.date=2005-05&rft_id=info:doi/10.1016/j.immuni.2005.03.012&rft_id=info:pmid/15894279&rft.aulast=Song&rft.aufirst=J&rft.au=So,+T&rft.au=Cheng,+M&rft.au=Tang,+X&rft.au=Croft,+M&rft_id=https://doi.org/10.1016%2Fj.immuni.2005.03.012&rfr_id=info:sid/en.wikipedia.org:CD134" class="Z3988">
• Croft M (August 2003). "Co-stimulatory members of the TNFR family: keys to effective T-cell immunity?". Nature Reviews. Immunology. 3 (8): 609–20. doi:10.1038/nri1148. PMID 12974476. S2CID 10503208.609-20&rft.date=2003-08&rft_id=https://api.semanticscholar.org/CorpusID:10503208#id-name=S2CID&rft_id=info:pmid/12974476&rft_id=info:doi/10.1038/nri1148&rft.aulast=Croft&rft.aufirst=M&rfr_id=info:sid/en.wikipedia.org:CD134" class="Z3988">
• Rogers PR, Song J, Gramaglia I, Killeen N, Croft M (September 2001). "OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells". Immunity. 15 (3): 445–55. doi:10.1016/S1074-7613(01)00191-1. PMID 11567634.445-55&rft.date=2001-09&rft_id=info:doi/10.1016/S1074-7613(01)00191-1&rft_id=info:pmid/11567634&rft.aulast=Rogers&rft.aufirst=PR&rft.au=Song,+J&rft.au=Gramaglia,+I&rft.au=Killeen,+N&rft.au=Croft,+M&rft_id=https://doi.org/10.1016%2FS1074-7613%2801%2900191-1&rfr_id=info:sid/en.wikipedia.org:CD134" class="Z3988">
• Watts TH (2005). "TNF/TNFR family members in costimulation of T cell responses". Annual Review of Immunology. 23: 23–68. doi:10.1146/annurev.immunol.23.021704.115839. PMID 15771565.23-68&rft.date=2005&rft_id=info:doi/10.1146/annurev.immunol.23.021704.115839&rft_id=info:pmid/15771565&rft.aulast=Watts&rft.aufirst=TH&rfr_id=info:sid/en.wikipedia.org:CD134" class="Z3988">