CD134

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

Function
OX40 has no effect on the proliferative abilities of is_associated_with::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 is_associated_with::Bcl-2, is_associated_with::Bcl-XL and is_associated_with::survivin. OX40 binds to receptors on T-cells, preventing them from dying and subsequently increasing is_associated_with::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 is_associated_with::Th2 mediated reactions is_associated_with::in vivo.

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

Clinical significance
OX40 has been implicated in the is_associated_with::pathologic is_associated_with::cytokine storm associated with certain viral infections, including the is_associated_with::H5N1 bird flu. An artificially created biologic is_associated_with::fusion protein, OX40-is_associated_with::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.

Interactions
CD134 has been shown to interact with is_associated_with::TRAF5 and is_associated_with::TRAF2.