CD134

{{Short description|Protein-coding gene in humans}} {{Infobox gene}} '''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.{{Citation needed|date=April 2016}}

==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.{{Citation needed|date=April 2016}}

An anti-OX40 antibody GSK3174998 has started clinical trials as a cancer treatment.<ref>{{Cite web |url=https://www.gsk.com/en-gb/media/press-releases/2015/gsk-and-merck-to-study-immunotherapy-combination-as-potential-cancer-treatment/ |title=GSK and Merck to study immunotherapy combination as potential cancer treatment. Nov 2015 |access-date=6 April 2016 |archive-url=https://web.archive.org/web/20170204065043/http://www.gsk.com/en-gb/media/press-releases/2015/gsk-and-merck-to-study-immunotherapy-combination-as-potential-cancer-treatment/ |archive-date=4 February 2017 }}</ref> 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.<ref name="Sagiv-BarfiCzerwinski2018">{{cite journal|vauthors = Sagiv-Barfi I, Czerwinski DK, Levy S, Alam IS, Mayer AT, Gambhir SS, Levy R |title = Eradication of spontaneous malignancy by local immunotherapy|journal = Science Translational Medicine|volume = 10|issue = 426|year = 2018|article-number = eaan4488|issn = 1946-6234|doi = 10.1126/scitranslmed.aan4488|pmid = 29386357|pmc = 5997264}}</ref>

== Interactions == CD134 has been shown to interact with TRAF5<ref name=pmid9488716>{{cite journal | vauthors = Kawamata S, Hori T, Imura A, Takaori-Kondo A, Uchiyama T | title = Activation of OX40 signal transduction pathways leads to tumor necrosis factor receptor-associated factor (TRAF) 2- and TRAF5-mediated NF-kappaB activation | journal = The Journal of Biological Chemistry | volume = 273 | issue = 10 | pages = 5808–14 | date = March 1998 | pmid = 9488716 | doi = 10.1074/jbc.273.10.5808 | doi-access = free }}</ref> and TRAF2.<ref name=pmid9418902>{{cite journal | vauthors = Arch RH, Thompson CB | title = 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 | journal = Molecular and Cellular Biology | volume = 18 | issue = 1 | pages = 558–65 | date = January 1998 | pmid = 9418902 | pmc = 121523 | doi = 10.1128/MCB.18.1.558 }}</ref>

== References == {{Reflist}}

== External links == * {{UCSC gene info|TNFRSF4}}

== Further reading == {{refbegin|35em}} * {{cite journal | vauthors = So T, Salek-Ardakani S, Nakano H, Ware CF, Croft M | title = TNF receptor-associated factor 5 limits the induction of Th2 immune responses | journal = Journal of Immunology | volume = 172 | issue = 7 | pages = 4292–7 | date = April 2004 | pmid = 15034043 | doi = 10.4049/jimmunol.172.7.4292 | doi-access = free }} * {{cite journal | vauthors = Song J, Salek-Ardakani S, Rogers PR, Cheng M, Van Parijs L, Croft M | title = The costimulation-regulated duration of PKB activation controls T cell longevity | journal = Nature Immunology | volume = 5 | issue = 2 | pages = 150–8 | date = February 2004 | pmid = 14730361 | doi = 10.1038/ni1030 | s2cid = 10102422 }} * {{cite journal | vauthors = Song J, So T, Cheng M, Tang X, Croft M | title = Sustained survivin expression from OX40 costimulatory signals drives T cell clonal expansion | journal = Immunity | volume = 22 | issue = 5 | pages = 621–31 | date = May 2005 | pmid = 15894279 | doi = 10.1016/j.immuni.2005.03.012 | doi-access = free }} * {{cite journal | vauthors = Croft M | title = Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? | journal = Nature Reviews. Immunology | volume = 3 | issue = 8 | pages = 609–20 | date = August 2003 | pmid = 12974476 | doi = 10.1038/nri1148 | s2cid = 10503208 }} * {{cite journal | vauthors = Rogers PR, Song J, Gramaglia I, Killeen N, Croft M | title = OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells | journal = Immunity | volume = 15 | issue = 3 | pages = 445–55 | date = September 2001 | pmid = 11567634 | doi = 10.1016/S1074-7613(01)00191-1 | doi-access = free }} * {{cite journal | vauthors = Watts TH | title = TNF/TNFR family members in costimulation of T cell responses | journal = Annual Review of Immunology | volume = 23 | pages = 23–68 | year = 2005 | pmid = 15771565 | doi = 10.1146/annurev.immunol.23.021704.115839 }} {{refend}}

{{DEFAULTSORT:Cd134}} Category:T cells Category:Clusters of differentiation