OX40 / CD134 is a member of the tumor necrosis factor (TNF) receptor family. It is part of a potent co-stimulatory pathway that when triggered can enhance T-cell memory, proliferation and antitumor activity in several preclinical cancer models as well as in humans thus overcoming some of the immunosuppressive properties of cancer.
Experiments with a soluble form of OX-40L / TNFSF4 / CD252 have shown that its engagement amplifies T cell proliferative responses to a range of stimuli. Activation does not affect early proliferation and activation but controls late proliferation and activation states. In vivo work has shown that OX40 / CD134 ligation preferentially expands the antigen-specific T cell pool.
Correspondingly, there is reduced CD4+ expansion in OX40 / CD134- or OX-40L / TNFSF4 / CD252 -deficient mice and constitutive OX40 / CD134- or OX-40L expression by either dendritic cells (DCs) or T cells results in a greater numbers of activated CD4+ T cells, and transfecting DCs with OX-40L / TNFSF4 / CD252 mRNA increases their CD4+ T cell stimulatory potency and increases T cell polarization. OX40 & OX40L immune checkpoint pathway results in augmentation of effector cytokine production and prolongation of activation, and this is partially mediated through stabilization of mRNA. An important mechanism by which T cells may prolong activation is through T cell-T cell interactions: by expression of both OX-40L / TNFSF4 / CD252 and OX40 / CD134 on activation, T cells may stimulate other T cells, so sustaining activation. Thus, proliferation is reduced in stimulated pure T cell cultures by OX-40L / TNFSF4 / CD252 blockade. An intriguing observation with relevance to autoimmunity is that T cells activated through OX40 / CD134 become resistant to subsequent regulation by Treg.
Gwilym J. Webb et al. OX40, OX40L and Autoimmunity: a Comprehensive Review. Clin Rev Allergy Immunol. 2015 Jul 28.
|Co-inhibitory immune checkpoint pathways||Co-stimulatory immune checkpoint pathways|
|PD1 & PD-L1 immune checkpoint pathway||CD40 & CD40L immune checkpoint pathway|
|CTLA-4 & CD80 (CD86) immune checkpoint pathway||CD266 & CD155 immune checkpoint pathway|
|B7-H3 / CD276 immune checkpoint pathway||HVEM & LIGHT immune checkpoint pathway|
|B7-H4 / B7S1 / B7x immune checkpoint pathway||CD28 & CD80 (CD86) immune checkpoint pathway|
|HVEM & BTLA immune checkpoint pathway||GITR & GITR Ligand immune checkpoint pathway|
|HVEM & CD160 immune checkpoint pathway||CD27 & CD70 immune checkpoint pathway|
|LAG3 / CD223 / Lymphocyte activation gene 3 immune checkpoint pathway||4-1BB & 4-1BBL immune checkpoint pathway|
|Galectin-9 & TIM-3 immune checkpoint pathway||ICOS & ICOS Ligand immune checkpoint pathway|
|Indoleamine 2,3-dioxygenase/IDO immune checkpoint pathway|
|VISTA / B7-H5 / GI24 immune checkpoint pathway|
|CEACAM1 / CD66a immune checkpoint pathway|
|SIRP alpha & CD47 immune checkpoint pathway|
|2B4 & CD48 immune checkpoint pathway|
|TIGIT & CD155 immune checkpoint pathway|