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.
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]
An anti-OX40 antibody GSK3174998 has started clinical trials as a cancer treatment.[4] 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.[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.
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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.
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