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OX40/OX40L Signaling Pathway


Figure 1. OX40/OX40L signaling pathway

Introduction

Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4), also known as CD134 and OX40 receptor, is a fellow of the TNFR-superfamily of receptors. It is a protein which in humans is encoded by the TNFRSF4 gene which contains 9 exons. It also has been demonstrated to have a key role in the survival and homeostasis of effector and memory T cells in transplantation and autoimmunity. OX40 is not constitutively expressed on resting naive T cells, unlike CD28. As a secondary co-stimulatory immune checkpoint molecule, it expresses after 24 to 72 hours following activation; its ligand, OX40L, is also not expressed on resting antigen presenting cells and resting naive T cells, but is following their activation. Expression of OX40 is dependent on full activation of the T cell and the expression of CD28; without CD28, expression of OX40 is delayed and of fourfold lower levels.

The function of pathway

According to previous introduction, OX40 is not expressed on resting T cells, but is upregulated reasonably late after T cell activation. OX40 is ligated by OX40L when activated T cells bind to APCs. 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(also known as Akt) activity and expression of Bcl-2, Bcl-XL and survivin (survivin protein functions to inhibit caspase activation, thereby leading to negative regulation of apoptosis or programmed cell death). OX40L binds to OX40 receptors on T-cells, preventing them from dying and subsequently increasing cytokine production. OX40 has a key 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. Besides, OX40 also plays a crucial role in both Th1 and Th2-mediated reactions in vivo. Therefore, quantitative and qualitative aspects of antigen specific T cell responses, including cytokine production, cytolytic function, expansion, and survival, are augmented by OX40 mediated costimulatory signals. In particular, research indicates that donor reactive memory T cells, which are resistant to CD28 and CD154 blockade in murine models of transplant rejection, are sensitive to OX40 blockade, thus supporting the idea that the OX40 pathway might be a promising therapeutic target for the attenuation of memory T cell mediated rejection. An additional interesting aspect of OX40 is the accumulating evidence that OX40 signals are essential for controlling the suppressive capacity of Foxp3+ Treg cells(Foxp3 a protein involved in immune system responses. It appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells). For example, ligation of OX40 on Foxp3+ Treg cells results in a loss of the ability of the Foxp3+ Treg cells to suppress effector T cell proliferation and IFN‑γ production, and precipitates allograft rejection, thus implicating OX40 as an important negative regulator of Foxp3+ Treg cell activity. After OX40 binding with its ligand, OX40L, OX40 recruits TRAF2, 3 and 5 as well as PI3K by an unknown mechanism. And then, signals are transmitted to the nucleus through IKKα/β/γ and Rel A/B, thereby regulating related genes, such as up-regulation of Bcl-2, Bcl-XL and survivin and down-regulation of Foxp3 and CTLA4. From previous studies, 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

Studies show OX40 is perhaps best appreciated for its decisive role in the development of airway inflammation and asthma. In model animal, OX40 knockout mice exhibit reduced lung inflammation and airway hyperreactivity compared with wild type control mice, possibly because of the requirement for OX40 in the development of allergenic TH2 and type 9 T helper cells (TH9) responses. This work stresses the importance of OX40 in the development of allergic asthma, and indicates that targeting OX40 could prove therapeutically useful. To date, one clinical trial has been completed using a humanized anti‑OX40L mAb (oxelumab) for the prevention of allergen induced airway inflammation and disease in adults with mild asthma. If oxelumab is beneficial to patients with mild asthma, this trial would spur the development of OX40L blockers for other indications in transplantation and autoimmunity. However, clinical trials of abatacept have taught us that distinct autoimmune pathologies might be differentially responsive to inhibition of individual costimulatory pathways and that assessment of OX40L blockers in patients with other autoimmune diseases and transplantation is warranted. Besides, OX40 has been involved in the pathologic cytokine storm associated with certain viral infections, including the H5N1 bird flu. 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 has started clinical trials as a cancer treatment. 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, in which a TLR9 ligand activates expression of OX40 so that it can be affected.

References:

1. Sagiv B. I., et al. Eradication of spontaneous malignancy by local immunotherapy. Science Translational Medicine. 2018,10 (426): eaan4488.
2. Kawamata S., et al. 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. 1998, 273 (10): 5808–14.
3. 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. 1998, 18 (1): 558–65.
4. Mandy L. F., et al. Targeting co-stimulatory pathways: transplantation and autoimmunity. Nature, 2014, 10: 14-24.

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