Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4), also known asCD134 andOX40 receptor, is a member of theTNFR-superfamily of receptors which is not constitutively expressed on resting naïveT cells, unlikeCD28. OX40 is a secondary co-stimulatoryimmune checkpoint molecule, expressed after 24 to 72 hours following activation; itsligand,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; withoutCD28, expression of OX40 is delayed and of fourfold lower levels.
OX40 has no effect on the proliferative abilities ofCD4+ 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 ofBcl-2,Bcl-XL andsurvivin. OX40L binds to OX40 receptors on T-cells, preventing them from dying and subsequently increasingcytokine 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 bothTh1 andTh2 mediated reactionsin vivo.
OX40 bindsTRAF2, 3 and 5 as well as PI3K by an unknown mechanism. TRAF2 is required for survival viaNF-κB and memory cell generation whereasTRAF5 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-mediatedmemory 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.
An artificially created biologicfusion 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]
An anti-OX40 antibody GSK3174998 has started clinical trials as a cancer treatment.[4] Research in mice has included the combination of anagonistic OX40 antibody (clone OX86) injected directly into a tumor in combination with an unmethylatedCpG oligonucleotide, which as aTLR9 ligand activates expression of OX40 so that it can be affected.[5]
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.PMID14730361.S2CID10102422.
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.PMID12974476.S2CID10503208.
