CD134 explained

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.^[1] 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.^[2]

Interactions

CD134 has been shown to interact with TRAF5^[3] and TRAF2.^[4]

Further reading

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

Notes and References

1. Web site: GSK and Merck to study immunotherapy combination as potential cancer treatment. Nov 2015 . 6 April 2016 . 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/ . 4 February 2017 . dead .
2. Sagiv-Barfi I, Czerwinski DK, Levy S, Alam IS, Mayer AT, Gambhir SS, Levy R . Eradication of spontaneous malignancy by local immunotherapy. Science Translational Medicine. 10. 426. 2018. eaan4488. 1946-6234. 10.1126/scitranslmed.aan4488. 29386357. 5997264.
3. Kawamata S, Hori T, Imura A, Takaori-Kondo A, Uchiyama T . 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 . March 1998 . 9488716 . 10.1074/jbc.273.10.5808 . free .
4. Arch RH, Thompson CB . 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 . January 1998 . 9418902 . 121523 . 10.1128/MCB.18.1.558 .