OX40 ligand

{{Short description|Protein family}}

{{infobox protein

|Name=tumor necrosis factor (ligand) superfamily, member 4 (tax-transcriptionally activated glycoprotein 1, 34kDa)

|caption=

|image=

|width=

|HGNCid=11934

|Symbol=TNFSF4

|AltSymbols=TXGP1, OX-40L, gp34, CD252

|EntrezGene=7292

|OMIM=603594

|RefSeq=NM_003326

|UniProt=P23510

|PDB=

|ECnumber=

|Chromosome=1

|Arm=q

|Band=25

|LocusSupplementaryData=

}}

OX40L is the ligand for OX40 (also known as CD134 or TNFRSF4) and is stably expressed on many antigen-presenting cells such as DC2s (a subtype of dendritic cells),{{cite journal | vauthors = Maizels RM, Yazdanbakhsh M | title = Immune regulation by helminth parasites: cellular and molecular mechanisms | journal = Nature Reviews. Immunology | volume = 3 | issue = 9 | pages = 733–44 | date = September 2003 | pmid = 12949497 | doi = 10.1038/nri1183 | hdl = 1842/465 | s2cid = 9323279 | url = http://www.era.lib.ed.ac.uk/bitstream/1842/465/1/Maizels_%26_Yazdanbakhsh.pdf | hdl-access = free }} macrophages,{{cite journal | vauthors = Lei W, Zeng DX, Zhu CH, Liu GQ, Zhang XQ, Wang CG, Wang Q, Huang JA | display-authors = 6 | title = The upregulated expression of OX40/OX40L and their promotion of T cells proliferation in the murine model of asthma | journal = Journal of Thoracic Disease | volume = 6 | issue = 7 | pages = 979–87 | date = July 2014 | pmid = 25093096 | pmc = 4120161 | doi = 10.3978/j.issn.2072-1439.2014.06.34 }} and activated B lymphocytes.{{cite journal | vauthors = Stüber E, Neurath M, Calderhead D, Fell HP, Strober W | title = Cross-linking of OX40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells | journal = Immunity | volume = 2 | issue = 5 | pages = 507–21 | date = May 1995 | pmid = 7749983 | doi = 10.1016/1074-7613(95)90031-4 | doi-access = free }}

The OX40 molecule, conversely, is present on the surface of activated T lymphocytes (mainly CD4+ T cells),{{cite journal | vauthors = Taraban VY, Rowley TF, O'Brien L, Chan HT, Haswell LE, Green MH, Tutt AL, Glennie MJ, Al-Shamkhani A | display-authors = 6 | title = Expression and costimulatory effects of the TNF receptor superfamily members CD134 (OX40) and CD137 (4-1BB), and their role in the generation of anti-tumor immune responses | journal = European Journal of Immunology | volume = 32 | issue = 12 | pages = 3617–27 | date = December 2002 | pmid = 12516549 | doi = 10.1002/1521-4141(200212)32:12<3617::AID-IMMU3617>3.0.CO;2-M | s2cid = 35148221 | doi-access = free }} but also on NK cells,{{cite journal | vauthors = Turaj AH, Cox KL, Penfold CA, French RR, Mockridge CI, Willoughby JE, Tutt AL, Griffiths J, Johnson PW, Glennie MJ, Levy R, Cragg MS, Lim SH | display-authors = 6 | title = Augmentation of CD134 (OX40)-dependent NK anti-tumour activity is dependent on antibody cross-linking | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 2278 | date = February 2018 | pmid = 29396470 | pmc = 5797108 | doi = 10.1038/s41598-018-20656-y | bibcode = 2018NatSR...8.2278T }} NKT cells,{{cite journal | vauthors = Croft M | title = Control of immunity by the TNFR-related molecule OX40 (CD134) | journal = Annual Review of Immunology | volume = 28 | issue = 1 | pages = 57–78 | date = March 2010 | pmid = 20307208 | pmc = 2882161 | doi = 10.1146/annurev-immunol-030409-101243 }} and neutrophils. The ligation of OX40-OX40L is a source of survival signal for T cells and enables the development of memory T cells.{{cite journal | vauthors = Frentsch M, Stark R, Matzmohr N, Meier S, Durlanik S, Schulz AR, Stervbo U, Jürchott K, Gebhardt F, Heine G, Reuter MA, Betts MR, Busch D, Thiel A | display-authors = 6 | title = CD40L expression permits CD8+ T cells to execute immunologic helper functions | journal = Blood | volume = 122 | issue = 3 | pages = 405–12 | date = July 2013 | pmid = 23719298 | pmc = 4548794 | doi = 10.1182/blood-2013-02-483586 }} Signaling through these two molecules also leads to polarization towards Th2 immune response even in an environment with low levels of IL-4 cytokine.{{cite book | first1 = Frederick W | last1 = Alt | first2 = K Frank | last2 = Austen | name-list-style = vanc |title=Advances in immunology | volume = 101 |date=2009 |publisher=Academic Press |isbn=978-0080888330 |location=Amsterdam |oclc=647803349 }}

OX40L is also present on the surface of many non-immune cells, for example, endothelial cells{{cite journal | vauthors = Imura A, Hori T, Imada K, Ishikawa T, Tanaka Y, Maeda M, Imamura S, Uchiyama T | display-authors = 6 | title = The human OX40/gp34 system directly mediates adhesion of activated T cells to vascular endothelial cells | journal = The Journal of Experimental Medicine | volume = 183 | issue = 5 | pages = 2185–95 | date = May 1996 | pmid = 8642328 | doi = 10.1084/jem.183.5.2185 | pmc = 2192546 }} and smooth muscle cells.{{cite journal | vauthors = Burgess JK, Carlin S, Pack RA, Arndt GM, Au WW, Johnson PR, Black JL, Hunt NH | display-authors = 6 | title = Detection and characterization of OX40 ligand expression in human airway smooth muscle cells: a possible role in asthma? | journal = The Journal of Allergy and Clinical Immunology | volume = 113 | issue = 4 | pages = 683–9 | date = April 2004 | pmid = 15100674 | doi = 10.1016/j.jaci.2003.12.311 }}

The surface expression of OX40L is induced by many pro-inflammatory mediators, such as TNF-α, e.g. produced by mast cells,{{cite journal | vauthors = Nakae S, Suto H, Iikura M, Kakurai M, Sedgwick JD, Tsai M, Galli SJ | title = Mast cells enhance T cell activation: importance of mast cell costimulatory molecules and secreted TNF | journal = Journal of Immunology | volume = 176 | issue = 4 | pages = 2238–48 | date = February 2006 | pmid = 16455980 | doi = 10.4049/jimmunol.176.4.2238 | s2cid = 22718354 | doi-access = free }} IFN-γ{{cite journal | vauthors = Wang Y, Li M, Song M, Xu X, Xiong J, Yang X, Tan J, Bai Y | display-authors = 6 | title = Expression of OX40 ligand in microglia activated by IFN-gamma sustains a protective CD4+ T-cell response in vitro | journal = Cellular Immunology | volume = 251 | issue = 2 | pages = 86–92 | date = February 2008 | pmid = 18485335 | doi = 10.1016/j.cellimm.2008.04.002 }} and PGE2 (prostaglandin E2).{{cite journal | vauthors = Krause P, Bruckner M, Uermösi C, Singer E, Groettrup M, Legler DF | title = Prostaglandin E(2) enhances T-cell proliferation by inducing the costimulatory molecules OX40L, CD70, and 4-1BBL on dendritic cells | journal = Blood | volume = 113 | issue = 11 | pages = 2451–60 | date = March 2009 | pmid = 19029446 | doi = 10.1182/blood-2008-05-157123 | s2cid = 43707862 | url = https://kops.uni-konstanz.de/bitstreams/2fe117bf-a574-4ce7-8635-6de891d253d5/download | doi-access = free }}

OX40L has also been designated CD252 (cluster of differentiation 252).{{UniProt Full|P23510|TNFSF4 - Tumor necrosis factor ligand superfamily member 4 - Homo sapiens (Human) }}

Various single-nucleotide polymorphisms (SNPs) of the OX40L gene have been identified. For some of them association with systemic lupus erythematosus has been reported.{{cite journal | vauthors = Lu MM, Xu WD, Yang J, Ye QL, Feng CC, Li J, Pan HF, Tao JH, Wang J, Ye DQ | display-authors = 6 | title = Association of TNFSF4 polymorphisms with systemic lupus erythematosus: a meta-analysis | journal = Modern Rheumatology | volume = 23 | issue = 4 | pages = 686–93 | date = July 2013 | pmid = 22850862 | doi = 10.3109/s10165-012-0708-8 | s2cid = 218988187 }} No association with occurrence of atherosclerosis has been found.{{cite journal | vauthors = Huang Q, Yang QD, Tan XL, Feng J, Tang T, Xia J, Zhang L, Huang L, Bai YP, Liu YH | display-authors = 6 | title = Absence of association between atherosclerotic cerebral infarction and TNFSF4/TNFRSF4 single nucleotide polymorphisms rs1234313, rs1234314 and rs17568 in a Chinese population | journal = The Journal of International Medical Research | volume = 42 | issue = 2 | pages = 436–43 | date = April 2014 | pmid = 24595151 | doi = 10.1177/0300060514521154 | s2cid = 35831673 | doi-access = free }}