OX40 Pathway
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OX40 Pathway

The OX40 costimulatory molecule is a member of the TNF receptor family and is expressed on activated CD4+ T cells and CD8+ T cells. OX40 ligand (OX40L) belongs to the TNF superfamily and is expressed on activated professional antigen-presenting cells such as DCs, macrophages, and B cells. OX40 signaling has been suggested to sustain the signaling pathways of the TCR, CD28, and the IL-2 receptor (Ref.1). Following antigen stimulation OX40 is transiently induced on activated naive CD4 and CD8 T cells. Although TCR signals are sufficient for inducing OX40, CD28-B7.1/2 interactions augment and sustain its expression, and T cell and APC-derived cytokines like IL-1, IL-2, and TNF may further modulate the extent and length of expression. T cell activation is initiated by recognition of peptide-major histocompatibility (MHC) complexes and the interaction of costimulatory receptors with their ligands present on the surface of antigen-presenting cells (APCs) (Ref.2).

OX40 activates PI3K/ PKB, NF-KappaB1, and NFAT pathways to allow both antigen-dependent and antigen-independent signaling. OX40 uses residues from cysteine-rich domain 1 (CRD1), CRD2, and CRD3 to bind OX40L. OX40 can recruit TNFR-associated factors (TRAF) 2, 3, and 5 to its cytoplasmic tail through a short stretch of conserved acids, which contain a QEE motif. The TRAF molecules are adaptor proteins thought to directly link to downstream kinases. TRAF2 appears to play a dominant role in mediating some of the functional effects of OX40. TRAF2 works as the primary signaling adaptor that links OX40 to NF-KappaB1. Activation of the NF-KappaB1 pathway is initiated by signal-dependent phosphorylation, ubiquitination, and subsequent degradation of IKappaBalpha, which allows cytoplasmic NF-KappaB1(p50)-RelA complexes to stably translocate to the nucleus and activate gene transcription. IKappaB-alpha phosphorylation is catalyzed by the IKappaB kinase (IKK) complex, that contains two homologous catalytic subunits, IKK-alpha and IKK-Beta, and the regulatory subunit IKK-Gamma. On the other hand, TRAF3 is believed to negatively regulate NF-KappaB activation (Ref.2) Triggering OX40 on T cells is responsible for prolonged activation of the PKB pathway, which in turn contributes to the high rate of clonal expansion of recently activated T cells. This cellular and molecular function regulated by the OX40-PKB axis is quite similar to that targeted by the OX40-NF-KappaB1 axis suggesting that PKB and NF-KappaB1 synergistically maintain T cell division and survival over time (Ref.3).

The mechanism of OX40/OX40L interaction may be related to the activation of phospholipase C (PLC) which induces diacylglycerol-protein kinase C (DAG-PKC) and the inositol trisphosphate (IP(3))-intracellular free calcium ([Ca(2+)](i)) pathway (Ref.4).The IP3-Ca2+ directly binds to nuclear factor of activated T (NFAT) transcription factors in the cytoplasm, resulting in their dephosphorylation and subsequent translocation into the nucleus. This translocation leads to diverse cellular physiological functions, such as secretion, cell proliferation, cell growth, differentiation and aging. NFATc1 is dephosphorylated by a Ca2+-dependent serine/threonine phosphatase, calcineurin, and then translocates into the nucleus where they associate with target DNA sequences (Ref.5). OX40 signals upregulate the expression of the anti apoptotic members of Bcl-2 family like Bcl2 and Bcxl and block programmed cell death due to cytokine/antigen withdrawal (Ref.6). OX40/OX40L strongly regulate conventional CD4 and CD8 T cells, and more recent data are highlighting their ability to modulate NKT cell and NK cell function as well as to mediate cross-talk with professional antigen-presenting cells and diverse cell types such as mast cells, smooth muscle cells, and endothelial cells. Additionally, OX40-OX40L interactions alter the differentiation and activity of regulatory T cells. Blocking OX40L has produced strong therapeutic effects in multiple animal models of autoimmune and inflammatory disease, and, in line with a prospective clinical future, reagents that stimulate OX40 signaling are showing promise as adjuvants for vaccination as well as for treatment of cancer (Ref.7).