Tumor necrosis factor receptor superfamily, member 4(TNFRSF4), also known asCD134andOX40 receptor,is a member of theTNFR-superfamily of receptors which is not constitutively expressed on resting naïveT cells,unlikeCD28.OX40 is a secondary co-stimulatoryimmune checkpointmolecule, expressed after 24 to 72 hours following activation; itsligand,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; withoutCD28,expression of OX40 is delayed and of fourfold lower levels.
Function
editOX40 has no effect on the proliferative abilities ofCD4+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 ofBcl-2,Bcl-XLandsurvivin.OX40L binds to OX40 receptors on T-cells, preventing them from dying and subsequently increasingcytokineproduction. 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 bothTh1andTh2mediated reactionsin vivo.
OX40 bindsTRAF2,3 and 5 as well as PI3K by an unknown mechanism. TRAF2 is required for survival viaNF-κBand memory cell generation whereasTRAF5seems to have a more negative or modulatory role, as knockouts have higher levels of cytokines and are more susceptible to Th2-mediated inflammation.TRAF3may play a critical role in OX40-mediated signal transduction.CTLA-4is 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-mediatedmemory T cellexpansion 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
editOX40 has been implicated in thepathologiccytokine stormassociated with certain viral infections, including theH5N1bird flu.[citation needed]
As a drug or drug target
editAn artificially created biologicfusion 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 anagonisticOX40 antibody (clone OX86) injected directly into a tumor in combination with an unmethylatedCpG oligonucleotide,which as aTLR9ligand activates expression of OX40 so that it can be affected.[5]
Interactions
editReferences
edit- ^abcGRCh38: Ensembl release 89: ENSG00000186827–Ensembl,May 2017
- ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^"GSK and Merck to study immunotherapy combination as potential cancer treatment. Nov 2015".Archived fromthe originalon 4 February 2017.Retrieved6 April2016.
- ^Sagiv-Barfi I, Czerwinski DK, Levy S, Alam IS, Mayer AT, Gambhir SS, Levy R (2018)."Eradication of spontaneous malignancy by local immunotherapy".Science Translational Medicine.10(426): eaan4488.doi:10.1126/scitranslmed.aan4488.ISSN1946-6234.PMC5997264.PMID29386357.
- ^Kawamata S, Hori T, Imura A, Takaori-Kondo A, Uchiyama T (March 1998)."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.273(10): 5808–14.doi:10.1074/jbc.273.10.5808.PMID9488716.
- ^Arch RH, Thompson CB (January 1998)."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.18(1): 558–65.doi:10.1128/MCB.18.1.558.PMC121523.PMID9418902.
External links
edit- HumanTNFRSF4genome location andTNFRSF4gene details page in theUCSC Genome Browser.
Further reading
edit- So T, Salek-Ardakani S, Nakano H, Ware CF, Croft M (April 2004)."TNF receptor-associated factor 5 limits the induction of Th2 immune responses".Journal of Immunology.172(7): 4292–7.doi:10.4049/jimmunol.172.7.4292.PMID15034043.
- 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.doi:10.1038/ni1030.PMID14730361.S2CID10102422.
- Song J, So T, Cheng M, Tang X, Croft M (May 2005)."Sustained survivin expression from OX40 costimulatory signals drives T cell clonal expansion".Immunity.22(5): 621–31.doi:10.1016/j.immuni.2005.03.012.PMID15894279.
- 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.PMID12974476.S2CID10503208.
- Rogers PR, Song J, Gramaglia I, Killeen N, Croft M (September 2001)."OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells".Immunity.15(3): 445–55.doi:10.1016/S1074-7613(01)00191-1.PMID11567634.
- Watts TH (2005). "TNF/TNFR family members in costimulation of T cell responses".Annual Review of Immunology.23:23–68.doi:10.1146/annurev.immunol.23.021704.115839.PMID15771565.