Alternative titles; symbols
HGNC Approved Gene Symbol: TNFRSF4
Cytogenetic location: 1p36.33 Genomic coordinates (GRCh38): 1:1,211,340-1,214,153 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.33 | ?Immunodeficiency 16 | 615593 | Autosomal recessive | 3 |
TNFRSF4 encodes a transmembrane protein belonging to the TNF receptor superfamily (see 191190). The TNFRSF4 protein is a costimulatory molecule implicated in long-term T-cell immunity (summary by Byun et al., 2013).
The ACT35 antigen is a cell surface glycoprotein that was discovered through the production of a monoclonal antibody raised against the HUT-102 cell line. Its expression can be induced on lymphocytes by mitogen stimulation or viral stimulation. Because the cell and tissue distribution resembles the pattern of the IL2 receptor, CD25 (147730), it was speculated that a relationship between the ACT35 antigen and the CD25 antigen exists. Latza et al. (1994) cloned a cDNA for the ACT35 antigen and showed its strong homology with the previously described rat OX40 antigen. It is therefore another member of the tumor necrosis factor/nerve growth factor receptor family. Birkeland et al. (1995) cloned cDNA and genomic DNA for the mouse homolog.
Byun et al. (2013) reported that the 277-amino acid human OX40 protein contains an N-terminal signal peptide, followed by 4 cysteine-rich domains, a transmembrane domain, and a C-terminal cytosolic domain.
Birkeland et al. (1995) determined the gene structure of mouse OX40, which showed that there are several intron/exon bodies shared between OX40 and CD27 (186711), CD40 (109535), TNFR1 (191190), and CD95 (134637).
By fluorescence in situ hybridization, Latza et al. (1994) mapped the ACT35 gene to 1p36, where the genes for TNFR2 (191191) and the lymphoid activation antigen CD30 (153243) are located.
Gross (2014) mapped the TNFRSF4 gene to chromosome 1p36.33 based on an alignment of the TNFRSF4 sequence (GenBank BC105070) with the genomic sequence (GRCh37).
Birkeland et al. (1995) mapped the gene encoding murine OX40 to chromosome 4 in an area that contains the gene for TNFR2 and shows homology of synteny with the region of human chromosome 1 that contains the genes for TNFR2, OX40, and CD30.
Song et al. (2004) showed that OX40 engagement sustains activation of protein kinase B (PKB; 164730) and intermediates of PKB signaling pathways, including PI3K (see 601232), GSK3 (see 606784), and FKHR (FOXO1A; 136533). T cells from mice lacking Ox40 were unable to maintain PKB activity over time, and this loss of activity coincided with cell death. Expression of active PKB in responding Ox40 -/- cells reversed the survival defect. Song et al. (2004) concluded that the duration of signaling needed for long-term survival is much longer than that needed for proliferation.
Munks et al. (2004) found that stimulation of 4-1BB (TNFRSF9; 602250) in mice at the time of a DNA prime, poxvirus vaccine, increased the number of functional memory CD8 (see 186910) T cells that responded, while stimulation of OX40 increased the number of antigen-specific CD4 (186940) T cells that responded. Stimulating both of these TNFRs enhanced the CD8 response more than stimulating 4-1BB alone. Munks et al. (2004) suggested that stimulating these receptors can improve the response to a powerful virus vector and may be useful in vaccine development.
Using flow cytometry and immunofluorescence microscopy, Jacquemin et al. (2015) observed high levels of OX40L expression by myeloid antigen-presenting cells (APCs) in inflamed pediatric tonsils and adult systemic lupus erythematosus (SLE; 152700) patient skin and kidney. OX40 signaling induced aberrant T follicular helper (Tfh) responses through upregulation of BCL6 (109565), CXCR5 (601613), IL21 (605384), CXCL13 (605149), and PDCD1 (600244) and downregulation of PRDM1 (603423) in SLE. The frequency of circulating OX40L-expressing myeloid APCs positively correlated with disease activity and the frequency of ICOS (604558)-positive Tfh cells in SLE. RNA-containing immune complexes induced OX40L expression on myeloid APCs via TLR7 (300365) activation. Jacquemin et al. (2015) proposed targeting the OX40-OX40L axis as a therapeutic modality for SLE.
Using a single dose of agonistic antibody against OX40, Bansal-Pakala et al. (2001) were able to prevent tolerance induction and to break existing tolerance or augment the reactivity of hyporesponsive T cells. Bansal-Pakala et al. (2001) proposed that targeting OX40 and possibly other members of the TNFR family might have benefits as adjuvants.
Byun et al. (2013) studied a 19-year-old Turkish woman with a primary immunodeficiency (IMD16; 615593) presenting as childhood-onset classic Kaposi sarcoma who had previously been reported as Case 3 by Sahin et al. (2010). Homozygosity mapping and whole-exome sequencing identified a homozygous arg65-to-cys (R65C; 600315.0001) mutation in the OX40 gene. The patient's consanguineous parents, a younger sister, and a younger brother were all heterozygous for R65C and HHV-8 seropositive, but they were free of Kaposi sarcoma. Byun et al. (2013) noted that the immunologic phenotype of the patient largely overlapped with that of mice lacking Ox40. Flow cytometric analysis demonstrated that OX40 with the R65C mutation was poorly expressed on T cells. Immunoblot analysis of activated control T cells showed expression of a 50-kD OX40 protein, with a minor fraction of 35 kD. However, in R65C heterozygotes and the homozygous patient, the 35-kD form, which was associated with immature carbohydrates and was exclusively intracellular, was predominant. The patient's T cells were unable to bind or respond to OX40L, indicating complete functional OX40 deficiency. All family members had a history of BCG vaccination, but only the patient's T cells failed to respond to tuberculin stimulation with IFNG (147570) production. Although seropositive for a number of recall antigens, the patient did not make a T-cell response to these antigens. Byun et al. (2013) proposed that the patient's high susceptibility to Kaposi sarcoma may have resulted from an inability to interact with OX40L, which is highly expressed on HHV-8-infected endothelial cells.
Using Ox40 -/- mice and a mouse model of asthma, Jember et al. (2001) found that wildtype mice had significantly higher eosinophilic infiltrate in the bronchial fluid than did Ox40 -/- mice. The Ox40-deficient mice also had significantly reduced levels of the Th2 cytokines IL4 (147780) and IL5 (147850), but no elevation in IFNG (147570), in bronchial fluid, and antigen-specific and total IgE was reduced in serum. Functional analysis indicated that wildtype mice had pronounced airway hyperreactivity compared with Ox40 -/- mice. Histologic analysis revealed marked cellular infiltrate around the bronchioles of wildtype mice and a near absence of mucus production by Ox40 -/- mice. Jember et al. (2001) concluded that OX40/OX40L interactions are integral to the development of the asthmatic phenotype. They proposed that strategies targeting both OX40 and CD28 (186760) may be most effective in preventing the development of allergen-specific T cells.
OX40 is not expressed on naive T cells, but it is upregulated within 2 days of antigen activation. Humphreys et al. (2003) showed that influenza virus-induced weight loss and T-cell inflammation in mice could be reduced by an Ox40-Ig fusion protein. Flow cytometric and intracellular cytokine analysis demonstrated that the number and proportion of Cd8-positive T cells producing Tnf were reduced in treated mice. Delayed treatment also inhibited weight loss in mice with established illness without affecting viral clearance or antigen recall responses. Reduced proliferation and enhanced apoptosis of lung cells accompanied the improved clinical phenotype. Humphreys et al. (2003) concluded that interference with the late costimulatory pathway has potential for the treatment of dysregulated immune responses in lung.
Shimojima et al. (2004) found that CD134 is the primary receptor for feline immunodeficiency virus. CD134 expression promotes viral binding and renders cells permissive for viral entry, productive infection, and syncytium formation. Infection is CXCR4 (162643)-dependent, analogous to infection with X4 strains of HIV.
In a Turkish woman with a primary immunodeficiency (IMD16; 615593) presenting as childhood-onset classic Kaposi sarcoma, Byun et al. (2013) identified homozygosity for a c.193C-T transition in the TNFRSF4 gene, resulting in an arg65-to-cys (R65C) substitution. The R65C substitution occurred in the first cysteine-rich domain in the extracellular region of OX40. R65 is not evolutionarily conserved, but it is adjacent to the highly conserved C64 residue that forms a disulfide bond with C46, suggesting that it may interrupt correct bond formation. The patient's consanguineous parents and 2 younger sibs were R65C heterozygotes and seropositive for HHV-8, the causative agent of Kaposi sarcoma, but they did not have Kaposi sarcoma. The R65C mutation was not found in 185 Turkish controls and 973 HGDP-CEPH individuals. Functional analysis showed poor expression of OX40 on T-cell surfaces and an inability to interact with or respond to OX40L (TNFSF4; 603594). T-cell responses to other recall antigens were poor; however, the patient had a history of successful cure of visceral leishmaniasis, caused by the intracellular parasite L. donovani (infantum).
Bansal-Pakala, P., Jember, A. G.-H., Croft, M. Signaling through OX40 (CD134) breaks peripheral T-cell tolerance. Nature Med. 7: 907-912, 2001. [PubMed: 11479622] [Full Text: https://doi.org/10.1038/90942]
Birkeland, M. L., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Barclay, A. N. Gene structure and chromosomal localization of the mouse homologue of rat OX40 protein. Europ. J. Immun. 25: 926-930, 1995. [PubMed: 7737295] [Full Text: https://doi.org/10.1002/eji.1830250410]
Byun, M., Ma, C. S., Akcay, A., Pedergnana, V., Palendira, U., Myoung, J., Avery, D. T., Liu, Y., Abhyankar, A., Lorenzo, L., Schmidt, M., Lim, H. K., and 17 others. Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood. J. Exp. Med. 210: 1743-1759, 2013. [PubMed: 23897980] [Full Text: https://doi.org/10.1084/jem.20130592]
Gross, M. B. Personal Communication. Baltimore, Md. 1/15/2014.
Humphreys, I. R., Walzl, G., Edwards, L., Rae, A., Hill, S., Hussell, T. A critical role for OX40 in T cell-mediated immunopathology during lung viral infection. J. Exp. Med. 198: 1237-1242, 2003. [PubMed: 14568982] [Full Text: https://doi.org/10.1084/jem.20030351]
Jacquemin, C., Schmitt, N., Contin-Bordes, C., Liu, Y., Narayanan, P., Seneschal, J., Maurouard, T., Dougall, D., Davizon, E. S., Dumortier, H., Douchet, I., Raffray, L., and 18 others. OX40 ligand contributes to human lupus pathogenesis by promoting T follicular helper response. Immunity 42: 1159-1170, 2015. [PubMed: 26070486] [Full Text: https://doi.org/10.1016/j.immuni.2015.05.012]
Jember, A. G.-H., Zuberi, R., Liu, F.-T., Croft, M. Development of allergic inflammation in a murine model of asthma is dependent on the costimulatory receptor OX40. J. Exp. Med. 193: 387-392, 2001. [PubMed: 11157058] [Full Text: https://doi.org/10.1084/jem.193.3.387]
Latza, U., Durkop, H., Schnittger, S., Ringeling, J., Eitelbach, F., Hummel, M., Fonatsch, C., Stein, H. The human OX40 homolog: cDNA structure, expression and chromosomal assignment of the ACT35 antigen. Europ. J. Immun. 24: 677-683, 1994. [PubMed: 7510240] [Full Text: https://doi.org/10.1002/eji.1830240329]
Munks, M. W., Mourich, D. V., Mittler, R. S., Weinberg, A. D., Hill, A. B. 4-1BB and OX40 stimulation enhance CD8 and CD4 T-cell responses to a DNA prime, poxvirus boost vaccine. Immunology 112: 559-566, 2004. [PubMed: 15270726] [Full Text: https://doi.org/10.1111/j.1365-2567.2004.01917.x]
Sahin, G., Palanduz, A., Aydogan, G., Cassar, O., Ertem, U., Telhan, L., Canpolat, N., Jouanguy, E., Picard, C., Gessain, A., Abel, L., Casanova, J.-L., Plancoulaine, S. Classic Kaposi sarcoma in 3 unrelated Turkish children born to consanguineous kindreds. Pediatrics 125: e704-e708, 2010. Note: Electronic Article. [PubMed: 20156905] [Full Text: https://doi.org/10.1542/peds.2009-2224]
Shimojima, M., Miyazawa, T., Ikeda, Y., McMonagle, E. L., Haining, H., Akashi, H., Takeuchi, Y., Hosie, M. J., Willett, B. J. Use of CD134 as a primary receptor by the feline immunodeficiency virus. Science 303: 1192-1195, 2004. [PubMed: 14976315] [Full Text: https://doi.org/10.1126/science.1092124]
Song, J., Salek-Ardakani, S., Rogers, P. R., Cheng, M., Van Parijs, L., Croft, M. The costimulation-regulated duration of PKB activation controls T cell longevity. Nature Immun. 5: 150-158, 2004. Note: Erratum: Nature Immun. 5: 1190 only, 2004. Erratum: Nature Immun. 6: 219 only, 2005. [PubMed: 14730361] [Full Text: https://doi.org/10.1038/ni1030]