CD134

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.

TNFRSF4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTNFRSF4, ACT35, CD134, IMD16, OX40, TXGP1L, tumor necrosis factor receptor superfamily member 4, TNF receptor superfamily member 4
External IDsOMIM: 600315 MGI: 104512 HomoloGene: 2496 GeneCards: TNFRSF4
Gene location (Human)
Chr.Chromosome 1 (human)[1]
Band1p36.33Start1,211,340 bp[1]
End1,214,153 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

7293

22163

Ensembl

ENSG00000186827

ENSMUSG00000029075

UniProt

P43489

P47741

RefSeq (mRNA)

NM_003327

NM_011659

RefSeq (protein)

NP_003318

NP_035789

Location (UCSC)Chr 1: 1.21 – 1.21 MbChr 4: 156.01 – 156.02 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5] 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.[6]

Interactions

CD134 has been shown to interact with TRAF5[7] and TRAF2.[8]

gollark: ```Little known fact: GHC compiles code by literally emailing it to the sixth circle of Hell, so no one knows how it works, not even the Type-level Deacons and other curators of scripture. The email address was revealed to the Haskell committee one moonless night when they sacrificed Simon Peyton Jones in an unholy ritual that they reenact every year at the monadic.party. The present-day SPJ is actually a decoy hired by FP Complete to preserve the illusion that anyone in the community even has a clue as to how to build working software.```
gollark: Well, things with more *features* might be slower.
gollark: oh, functions!
gollark: ... not that I know of.
gollark: /coroutine.

References

  1. GRCh38: Ensembl release 89: ENSG00000186827 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000029075 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "GSK and Merck to study immunotherapy combination as potential cancer treatment. Nov 2015". Archived from the original on 4 February 2017. Retrieved 6 April 2016.
  6. Sagiv-Barfi I, Czerwinski DK, Levy S, Alam IS, Mayer AT, Gambhir SS, Levy R (2018). "Eradication of spontaneous malignancy by local immunotherapy". Science Translational Medicine. 10 (426): eaan4488. doi:10.1126/scitranslmed.aan4488. ISSN 1946-6234. PMC 5997264. PMID 29386357.
  7. Kawamata S, Hori T, Imura A, Takaori-Kondo A, Uchiyama T (March 1998). "Activation of OX40 signal transduction pathways leads to tumor necrosis factor receptor-associated factor (TRAF) 2- and TRAF5-mediated NF-kappaB activation". The Journal of Biological Chemistry. 273 (10): 5808–14. doi:10.1074/jbc.273.10.5808. PMID 9488716.
  8. Arch RH, Thompson CB (January 1998). "4-1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor kappaB". Molecular and Cellular Biology. 18 (1): 558–65. doi:10.1128/MCB.18.1.558. PMC 121523. PMID 9418902.

Further reading

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