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 ==