OX40 ligand

Last updated
tumor necrosis factor (ligand) superfamily, member 4 (tax-transcriptionally activated glycoprotein 1, 34kDa)
Identifiers
SymbolTNFSF4
Alt. symbolsTXGP1, OX-40L, gp34, CD252
NCBI gene 7292
HGNC 11934
OMIM 603594
RefSeq NM_003326
UniProt P23510
Other data
Locus Chr. 1 q25
Search for
Structures Swiss-model
Domains InterPro

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), [1] macrophages, [2] and activated B lymphocytes. [3]

The OX40 molecule, conversely, is present on the surface of activated T lymphocytes (mainly CD4+ T cells), [4] but also on NK cells, [5] NKT cells, [6] and neutrophils. [6] The ligation of OX40-OX40L is a source of survival signal for T cells [6] and enables the development of memory T cells. [7] Signaling through these two molecules also leads to polarization towards Th2 immune response even in an environment with low levels of IL-4 cytokine. [1] [8]

OX40L is also present on the surface of many non-immune cells, for example, endothelial cells [9] and smooth muscle cells. [10]

The surface expression of OX40L is induced by many pro-inflammatory mediators, such as TNF-α, e.g. produced by mast cells, [11] IFN-γ [12] and PGE2 (prostaglandin E2). [13]

OX40L has also been designated CD252 (cluster of differentiation 252). [14]

Various single-nucleotide polymorphisms (SNPs) of the OX40L gene have been identified. For some of them association with systemic lupus erythematosus has been reported. [15] No association with occurrence of atherosclerosis has been found. [16]

Related Research Articles

<span class="mw-page-title-main">CD40 (protein)</span> Mammalian protein found in Homo sapiens

Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

Co-stimulation is a secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell. In the case of T cells, two stimuli are required to fully activate their immune response. During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.

<span class="mw-page-title-main">CD154</span> Protein-coding gene in humans

CD154, also called CD40 ligand or CD40L, is a protein that is primarily expressed on activated T cells and is a member of the TNF superfamily of molecules. It binds to CD40 on antigen-presenting cells (APC), which leads to many effects depending on the target cell type. In total CD40L has three binding partners: CD40, α5β1 integrin and integrin αIIbβ3. CD154 acts as a costimulatory molecule and is particularly important on a subset of T cells called T follicular helper cells. On TFH cells, CD154 promotes B cell maturation and function by engaging CD40 on the B cell surface and therefore facilitating cell-cell communication. A defect in this gene results in an inability to undergo immunoglobulin class switching and is associated with hyper IgM syndrome. Absence of CD154 also stops the formation of germinal centers and therefore prohibiting antibody affinity maturation, an important process in the adaptive immune system.

<span class="mw-page-title-main">Interleukin 19</span> Protein-coding gene in the species Homo sapiens

Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.

<span class="mw-page-title-main">CD80</span> Mammalian protein found in Homo sapiens

The Cluster of differentiation 80 is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is closely related to CD86, another B7 protein (B7-2), and often works in tandem. Both CD80 and CD86 interact with costimulatory receptors CD28, CTLA-4 (CD152) and the p75 neurotrophin receptor.

<span class="mw-page-title-main">CD86</span> Mammalian protein found in Homo sapiens

Cluster of Differentiation 86 is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells, and on other antigen-presenting cells. Along with CD80, CD86 provides costimulatory signals necessary for T cell activation and survival. Depending on the ligand bound, CD86 can signal for self-regulation and cell-cell association, or for attenuation of regulation and cell-cell disassociation.

<span class="mw-page-title-main">CD134</span> Protein-coding gene in humans

Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4), also known as CD134 and OX40 receptor, is a member of the TNFR-superfamily of receptors which is not constitutively expressed on resting naïve T cells, unlike CD28. OX40 is a secondary co-stimulatory immune checkpoint molecule, expressed after 24 to 72 hours following activation; its ligand, 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; without CD28, expression of OX40 is delayed and of fourfold lower levels.

CD70 is a protein that in humans is encoded by CD70 gene. CD70 is also known as a ligand for CD27.

<span class="mw-page-title-main">CD137</span> Member of the tumor necrosis factor (TNF) receptor family

CD137, a member of the tumor necrosis factor (TNF) receptor family, is a type 1 transmembrane protein, expressed on surfaces of leukocytes and non-immune cells. Its alternative names are tumor necrosis factor receptor superfamily member 9 (TNFRSF9), 4-1BB, and induced by lymphocyte activation (ILA). It is of interest to immunologists as a co-stimulatory immune checkpoint molecule, and as a potential target in cancer immunotherapy.

<span class="mw-page-title-main">Toll-like receptor 4</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 4 (TLR4), also designated as CD284, is a transmembrane protein of approximately 95 kDa that is encoded by the TLR4 gene.

<span class="mw-page-title-main">PD-L1</span> Mammalian protein found in humans

Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.

<span class="mw-page-title-main">CD244</span> Protein found in humans

CD244 also known as 2B4 or SLAMF4 is a protein that in humans is encoded by the CD244 gene.

<span class="mw-page-title-main">ICOSLG</span> Protein-coding gene in the species Homo sapiens

ICOS ligand is a protein that in humans is encoded by the ICOSLG gene located at chromosome 21. ICOSLG has also been designated as CD275.

<span class="mw-page-title-main">PDCD1LG2</span> Protein-coding gene in the species Homo sapiens

Programmed cell death 1 ligand 2 is a protein that in humans is encoded by the PDCD1LG2 gene. PDCD1LG2 has also been designated as CD273. PDCD1LG2 is an immune checkpoint receptor ligand which plays a role in negative regulation of the adaptive immune response. PD-L2 is one of two known ligands for Programmed cell death protein 1 (PD-1).

<span class="mw-page-title-main">CD200</span> Protein-coding gene in the species Homo sapiens

OX-2 membrane glycoprotein, also named CD200 is a human protein encoded by the CD200 gene. CD200 gene is in human located on chromosome 3 in proximity to genes encoding other B7 proteins CD80/CD86. In mice CD200 gene is on chromosome 16.

<span class="mw-page-title-main">TNFRSF18</span> Protein-coding gene in the species Homo sapiens

Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR) or CD357. GITR is encoded and tnfrsf18 gene at chromosome 4 in mice. GITR is type I transmembrane protein and is described in 4 different isoforms. GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the TNFRSF18 gene at chromosome 1.

<span class="mw-page-title-main">NKG2D</span> Protein-coding gene in the species Homo sapiens

NKG2D is an activating receptor (transmembrane protein) belonging to the NKG2 family of C-type lectin-like receptors. NKG2D is encoded by KLRK1 (killer cell lectin like receptor K1) gene which is located in the NK-gene complex (NKC) situated on chromosome 6 in mice and chromosome 12 in humans. In mice, it is expressed by NK cells, NK1.1+ T cells, γδ T cells, activated CD8+ αβ T cells and activated macrophages. In humans, it is expressed by NK cells, γδ T cells and CD8+ αβ T cells. NKG2D recognizes induced-self proteins from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells.

<span class="mw-page-title-main">Immune checkpoint</span> Regulators of the immune system

Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulating immune checkpoint targets.

Tolerogenic dendritic cells are heterogenous pool of dendritic cells with immuno-suppressive properties, priming immune system into tolerogenic state against various antigens. These tolerogenic effects are mostly mediated through regulation of T cells such as inducing T cell anergy, T cell apoptosis and induction of Tregs. Tol-DCs also affect local micro-environment toward tolerogenic state by producing anti-inflammatory cytokines.

<span class="mw-page-title-main">CD28 family receptor</span> Group of regulatory cell surface receptors

CD28 family receptors are a group of regulatory cell surface receptors expressed on immune cells. The CD28 family in turn is a subgroup of the immunoglobulin superfamily.

References

  1. 1 2 Maizels RM, Yazdanbakhsh M (September 2003). "Immune regulation by helminth parasites: cellular and molecular mechanisms" (PDF). Nature Reviews. Immunology. 3 (9): 733–44. doi:10.1038/nri1183. hdl: 1842/465 . PMID   12949497. S2CID   9323279.
  2. ↑ Lei W, Zeng DX, Zhu CH, Liu GQ, Zhang XQ, Wang CG, et al. (July 2014). "The upregulated expression of OX40/OX40L and their promotion of T cells proliferation in the murine model of asthma". Journal of Thoracic Disease. 6 (7): 979–87. doi:10.3978/j.issn.2072-1439.2014.06.34. PMC   4120161 . PMID   25093096.
  3. ↑ Stüber E, Neurath M, Calderhead D, Fell HP, Strober W (May 1995). "Cross-linking of OX40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells". Immunity. 2 (5): 507–21. doi: 10.1016/1074-7613(95)90031-4 . PMID   7749983.
  4. ↑ Taraban VY, Rowley TF, O'Brien L, Chan HT, Haswell LE, Green MH, et al. (December 2002). "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". European Journal of Immunology. 32 (12): 3617–27. doi: 10.1002/1521-4141(200212)32:12<3617::AID-IMMU3617>3.0.CO;2-M . PMID   12516549. S2CID   35148221.
  5. ↑ Turaj AH, Cox KL, Penfold CA, French RR, Mockridge CI, Willoughby JE, et al. (February 2018). "Augmentation of CD134 (OX40)-dependent NK anti-tumour activity is dependent on antibody cross-linking". Scientific Reports. 8 (1): 2278. Bibcode:2018NatSR...8.2278T. doi:10.1038/s41598-018-20656-y. PMC   5797108 . PMID   29396470.
  6. 1 2 3 Croft M (March 2010). "Control of immunity by the TNFR-related molecule OX40 (CD134)". Annual Review of Immunology. 28 (1): 57–78. doi:10.1146/annurev-immunol-030409-101243. PMC   2882161 . PMID   20307208.
  7. ↑ Frentsch M, Stark R, Matzmohr N, Meier S, Durlanik S, Schulz AR, et al. (July 2013). "CD40L expression permits CD8+ T cells to execute immunologic helper functions". Blood. 122 (3): 405–12. doi:10.1182/blood-2013-02-483586. PMC   4548794 . PMID   23719298.
  8. ↑ Alt FW, Austen KF (2009). Advances in immunology. Vol. 101. Amsterdam: Academic Press. ISBN   978-0080888330. OCLC   647803349.
  9. ↑ Imura A, Hori T, Imada K, Ishikawa T, Tanaka Y, Maeda M, et al. (May 1996). "The human OX40/gp34 system directly mediates adhesion of activated T cells to vascular endothelial cells". The Journal of Experimental Medicine. 183 (5): 2185–95. doi:10.1084/jem.183.5.2185. PMC   2192546 . PMID   8642328.
  10. ↑ Burgess JK, Carlin S, Pack RA, Arndt GM, Au WW, Johnson PR, et al. (April 2004). "Detection and characterization of OX40 ligand expression in human airway smooth muscle cells: a possible role in asthma?". The Journal of Allergy and Clinical Immunology. 113 (4): 683–9. doi:10.1016/j.jaci.2003.12.311. PMID   15100674.
  11. ↑ Nakae S, Suto H, Iikura M, Kakurai M, Sedgwick JD, Tsai M, Galli SJ (February 2006). "Mast cells enhance T cell activation: importance of mast cell costimulatory molecules and secreted TNF". Journal of Immunology. 176 (4): 2238–48. doi: 10.4049/jimmunol.176.4.2238 . PMID   16455980. S2CID   22718354.
  12. ↑ Wang Y, Li M, Song M, Xu X, Xiong J, Yang X, et al. (February 2008). "Expression of OX40 ligand in microglia activated by IFN-gamma sustains a protective CD4+ T-cell response in vitro". Cellular Immunology. 251 (2): 86–92. doi:10.1016/j.cellimm.2008.04.002. PMID   18485335.
  13. ↑ Krause P, Bruckner M, Uermösi C, Singer E, Groettrup M, Legler DF (March 2009). "Prostaglandin E(2) enhances T-cell proliferation by inducing the costimulatory molecules OX40L, CD70, and 4-1BBL on dendritic cells". Blood. 113 (11): 2451–60. doi: 10.1182/blood-2008-05-157123 . PMID   19029446. S2CID   43707862.
  14. ↑ Universal protein resource accession number P23510 for "TNFSF4 - Tumor necrosis factor ligand superfamily member 4 - Homo sapiens (Human) " at UniProt.
  15. ↑ Lu MM, Xu WD, Yang J, Ye QL, Feng CC, Li J, et al. (July 2013). "Association of TNFSF4 polymorphisms with systemic lupus erythematosus: a meta-analysis". Modern Rheumatology. 23 (4): 686–93. doi:10.3109/s10165-012-0708-8. PMID   22850862. S2CID   218988187.
  16. ↑ Huang Q, Yang QD, Tan XL, Feng J, Tang T, Xia J, et al. (April 2014). "Absence of association between atherosclerotic cerebral infarction and TNFSF4/TNFRSF4 single nucleotide polymorphisms rs1234313, rs1234314 and rs17568 in a Chinese population". The Journal of International Medical Research. 42 (2): 436–43. doi: 10.1177/0300060514521154 . PMID   24595151. S2CID   35831673.
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