Alternative titles; symbols
HGNC Approved Gene Symbol: TOX
Cytogenetic location: 8q12.1 Genomic coordinates (GRCh38) : 8:58,805,412-59,119,147 (from NCBI)
Some high-mobility group (HMG) box proteins (e.g., LEF1; 153245) contain a single HMG box motif and bind DNA in a sequence-specific manner, while other members of this family (e.g., HMG1; 163905) have multiple HMG boxes and bind DNA in a sequence-independent but structure-dependent manner. All HMG box proteins are able to induce a sharp bend in DNA. TOX contains a single HMG box motif (Wilkinson et al., 2002).
By screening for cDNAs with the potential to encode large proteins expressed in brain, Nagase et al. (1998) identified a cDNA encoding KIAA0808. The 526-amino acid protein was predicted to be 47% identical to CAGF9 (TOX3; 611416) over 238 residues. RT-PCR analysis detected weak expression in all tissues tested, with highest levels in testis, ovary, and brain.
Using gene chip analysis of mouse CD4 (186940)/CD8 (see 186910) double-positive thymocytes undergoing differentiation in culture, Wilkinson et al. (2002) identified a mouse cDNA encoding Tox, a 526-residue protein that is 94% identical to KIAA0808. The predicted Tox protein contains a central, completely conserved putative bipartite nuclear localization sequence N-terminal to a 69-amino acid HMG box motif. Fluorescence microscopy demonstrated nuclear expression of Tox in the presence or absence of the HMG motif. Immunoblot analysis showed expression of a predicted 57-kD protein as well as a 63-kD form that probably arose from posttranslation modification. Northern blot analysis revealed expression of a major 3.0-kb transcript and a minor 4.0-kb transcript in thymus, notably in immature double-positive thymocytes, with lower expression in liver and brain and little or no expression in other tissues tested. Flow cytometric analysis showed highest levels of expression in early double-negative thymocytes.
Wilkinson et al. (2002) found that mice transgenically expressing Tox exhibited an increase in CD8-positive single-positive thymocytes, a corresponding decrease in CD4-positive single-positive cells, and a concomitant alteration in T-cell receptor (see 186880) lineage commitment with reduced CD5 (153340) expression.
Khan et al. (2019) identified the HMG-box transcription factor TOX as a central regulator of exhausted CD8+ T cells in mice. TOX is largely dispensable for the formation of effector T cells and memory T cells, but it is critical for exhaustion: in the absence of TOX, exhausted CD8+ T cells do not form. TOX is induced by calcineurin (see 114105) and NFAT2 (600489), and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in exhausted T cells. Robust expression of TOX therefore results in commitment to exhausted T cells by translating persistent stimulation into a distinct exhausted CD8+ T cell transcriptional and epigenetic developmental program.
Alfei et al. (2019) reported that the development and maintenance of populations of exhausted T cells in mice requires the TOX protein. TOX is induced by high antigen stimulation of the T cell receptor and correlates with the presence of an exhausted phenotype during chronic infections with lymphocytic choriomeningitis virus in mice and hepatitis C virus in humans. Removal of its DNA-binding domain reduces the expression of PD1 (600244) at the mRNA and protein level, augments the production of cytokines, and results in a more polyfunctional T cell phenotype. T cells with this deletion initially mediate increased effector function and cause more severe immunopathology, but ultimately undergo a massive decline in their quantity, notably among the subset of TCF1 (189908)+ self-renewing T cells. Alfei et al. (2019) concluded that they demonstrated that TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infection, and provide a link between the suppression of effector function intrinsic to CD8 T cells and protection against immunopathology.
Scott et al. (2019) identified the nuclear factor TOX as a crucial regulator of the differentiation of tumor-specific T (TST) cells. They showed that TOX is highly expressed in dysfunctional TST cells from tumors and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of TOX in TST cells in tumors abrogated the exhaustion program: TOX-deleted TST cells did not upregulate genes for inhibitory receptors, such as PDCD1 (600244), ENTPD1 (601752), HAVCR2 (606652), CD244 (605554), and TIGIT (612859), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF1. Despite their normal, nonexhausted immunophenotype, TOX-deleted TST cells remained dysfunctional, which suggested that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although TOX-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, TOX-deleted TST cells failed to persist in tumors. Scott et al. (2019) hypothesized that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer.
Gross (2013) mapped the TOX gene to chromosome 8q12.1 based on an alignment of the TOX sequence (GenBank BC016665) with the genomic sequence (GRCh37).
Associations Pending Confirmation
Grant et al. (2013) used a positional cloning approach for fine linkage-disequilibrium mapping of a pulmonary tuberculosis (PTB) susceptibility locus on chromosome 8q12-q13 (MTBS2; 611046). They genotyped 3,216 SNPs in 203 nuclear families from Morocco that included 286 offspring with PTB. The 44 PTB-associated SNPs identified in this sample were then genotyped in an independent set of 317 cases and 650 controls from Morocco. A single signal, consisting of 2 correlated SNPs, rs1568952 (combined p =1.1 x 10(-5)) and rs2726600 (combined p = 9.2 x 10(-5)), located in the 3-prime UTR and intron 8 of TOX, respectively, was replicated. The association with rs1568952 was stronger in individuals who developed PTB before age 25 years (combined p = 4.4 x 10(-8)), giving an odds ratio of developing PTB for AA versus AG or GG genotypes of 3.09. The association of rs2726600 with PTB was subsequently replicated in individuals under age 25 years from 243 nuclear families from Madagascar that included 244 offspring with PTB (p = 0.04). Additional SNPs, including rs2726597, in strong linkage disequilibrium with the 2 original SNPs provided stronger evidence of replication in the Madagascar population, further confirming the signal. Grant et al. (2013) concluded that a cluster of SNPs around rs1568952 and rs2726600, near the 3-prime end of the TOX gene, are strongly associated with early-onset PTB in 2 geographically and ethnically distinct populations in Morocco and Madagascar.
Alfei, F., Kanev, K., Hofmann, M., Wu, M., Ghoneim, H. E., Roelli, P., Utzschneider, D. T., von Hoesslin, M., Cullen, J. G., Fan, Y., Eisenberg, V., Wohlleber, D., Steiger, K., Merkler, D., Delorenzi, M., Knolle, P. A., Cohen, C. J., Thimme, R., Youngblood, B., Zehn, D. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571: 265-269, 2019. [PubMed: 31207605] [Full Text: https://doi.org/10.1038/s41586-019-1326-9]
Grant, A. V., El Baghdadi, J., Sabri, A., El Azbaoui, S., Alaoui-Tahiri, K., Rhorfi, I. A., Gharbaoui, Y., Abid, A., Benkirane, M., Raharimanga, V., Richard, V., Orlova, M., and 11 others. Age-dependent association between pulmonary tuberculosis and common TOX variants in the 8q12-13 linkage region. Am. J. Hum. Genet. 92: 407-414, 2013. [PubMed: 23415668] [Full Text: https://doi.org/10.1016/j.ajhg.2013.01.013]
Gross, M. B. Personal Communication. Baltimore, Md. 5/7/2013.
Khan, O., Giles, J. R., McDonald, S., Manne, S., Ngiow, S. F., Patel, K. P., Werner, M. T., Huang, A. C., Alexander, K. A., Wu, J. E., Attanasio, J., Yan, P., and 13 others. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571: 211-218, 2019. [PubMed: 31207603] [Full Text: https://doi.org/10.1038/s41586-019-1325-x]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 277-286, 1998. [PubMed: 9872452] [Full Text: https://doi.org/10.1093/dnares/5.5.277]
Scott, A. C., Dundar, F., Zumbo, P., Chandran, S. S., Klebanoff, C. A., Shakiba, M., Trivedi, P., Menocal, L., Appleby, H., Camara, S., Zamarin, D., Walther, T., and 15 others. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571: 270-274, 2019. [PubMed: 31207604] [Full Text: https://doi.org/10.1038/s41586-019-1324-y]
Wilkinson, B., Chen, J. Y.-F., Han, P., Rufner, K. M., Goularte, O. D., Kaye, J. TOX: an HMG box protein implicated in the regulation of thymocyte selection. Nature Immun. 3: 272-280, 2002. [PubMed: 11850626] [Full Text: https://doi.org/10.1038/ni767]