Alternative titles; symbols
HGNC Approved Gene Symbol: TCF7
Cytogenetic location: 5q31.1 Genomic coordinates (GRCh38): 5:134,108,218-134,148,210 (from NCBI)
Three of the genes determining subunits of the CD3 complex, CD3-gamma (CD3G; 186740), CD3-delta (CD3D; 186790), and CD3-epsilon (CD3E; 186830), are tightly clustered in a stretch of 60 kb of DNA on human chromosome 11q23. This tight clustering might suggest that the CD3 genes are controlled by a single cis-acting element. Experiments with transgenic mice, however, have shown that at least the CD3D and CD3E genes carry a complete and independent set of regulatory elements. CD3E gene expression appears to be controlled by a downstream T lymphocyte-specific enhancer element. By screening for proteins in human T cells that bound the T lymphocyte-specific enhancer element downstream of CD3E, followed by screening human T-cell line cDNA libraries, van de Wetering et al. (1991) cloned 3 splice variants of TCF7, which they called TCF1A, TCF1B, and TCF1C. The deduced proteins contain 269, 269, and 268 amino acids, respectively. Each has an N-terminal proline-rich domain, followed by an HMG1 (HMGB1; 163905)-like DNA-binding domain and a unique C-terminal end. Northern blot analysis detected a 3-kb transcript in all human T-cell lines examined, but not in non-T cell lines.
Van de Wetering et al. (1992) stated that the HMG box domain of TCF7 is almost identical to the HMG box domain of TCF1-alpha (LEF1; 153245).
Van de Wetering et al. (1996) cloned several additional TCF7 splice variants encoding at least 8 TCF7 isoforms. The isoforms differ predominantly in the presence or absence of a long N-terminal domain, the presence or absence of an insertion near the center of the molecule, and the presence or absence of a long C-terminal domain. The 116-amino acid long N-terminal domain shares significant similarity with LEF1. Western blot analysis of human thymocytes and Jurkat T cells showed proteins with apparent molecular masses of 25 to 55 kD. Dephosphorylation did not alter the mobility of the proteins.
Van de Wetering et al. (1992) found that the TCF7 gene contains at least 10 exons, the first of which is noncoding. The region immediately upstream of exon 1 is CG rich (75%) and includes a CpG island. The CpG island coincided with a functional promoter that was preferentially active in T-cell lines.
Van de Wetering et al. (1996) determined that the TCF7 gene spans about 12 kb and contains 14 exons, 4 of which are alternatively spliced. It has 2 promoter regions and 2 transcriptional start sites.
Van de Wetering et al. (1991) mapped the TCF7 gene to chromosome 5q31.1 by somatic cell hybrid analysis and fluorescence in situ hybridization.
Kingsmore et al. (1995) mapped the homologous gene to mouse chromosome 11.
Using a gel retardation assay, van de Wetering et al. (1991) showed that all 3 recombinant isoforms of TCF7, which they called TCF1A, TCF1B, and TCF1C, bound the same motif in the T lymphocyte-specific enhancer element downstream of CD3E. Following expression in COS cells, full-length TCF1A, but not TCF1A lacking part of its DNA-binding domain, activated transcription of a reporter gene.
Van de Wetering et al. (1996) showed that all TCF7 isoforms with the short N-terminal end moderately transactivated transcription through the TCR-alpha (TCRA; see 186880) enhancer, a LEF1 target. In contrast, TCF7 isoforms with the long N-terminal end showed no transactivation activity.
Roose et al. (1999) identified TCF7 mRNA by Northern blot analysis in 5 of 6 colorectal cell lines. Three of these were APC (611731) mutants, and 2 others carried oncogenic mutations in beta-catenin (CTNNB1; 116806). The cell line that lacked TCF7 expression was wildtype for APC and beta-catenin, suggesting that APC and beta-catenin may regulate TCF7 expression. Roose et al. (1999) also detected nuclear TCF7 protein in normal human tissues: in proliferating intestinal epithelial cells and in the basal epithelial cells of mammary gland epithelium. Roose et al. (1999) noted that the most abundant TCF7 isoforms lack a beta-catenin interaction domain and are likely to function as negative regulators of Wnt signaling (see 164820). Roose et al. (1999) identified TCF7 as one of the target genes of TCF4 (TCF7L2; 602228) in epithelial cells. They found a putative enhancer upstream of promoter 1 of TCF7. Reporter assays showed that a combination of TCF4 and beta-catenin transactivated the enhancer, whereas a dominant-negative TCF4 inhibited enhancer activity.
Gattinoni et al. (2009) reported that induction of Wnt/beta-catenin signaling by inhibitors of Gsk3b (605004) or by Wnt3a (606359) arrested mouse Cd8 (see 186910)-positive T-cell development into effector T cells capable of cytotoxicity or Ifng (147570) production. Instead, Wnt signaling promoted expression of Tcf7 and Lef1 (153245) and generation of self-renewing multipotent Cd8-positive memory stem cells capable of proliferation and antitumor activity. Gattinoni et al. (2009) concluded that Wnt signaling has a key role in maintaining the self-renewing stem cell-like properties of mature memory CD8-positive T cells.
Using RT-PCR and flow cytometric analysis, Zhao et al. (2010) demonstrated that mouse Tcf7 and Lef1 were highly expressed in naive T cells, downregulated in effector T cells, and upregulated in memory T cells. Memory Cd8-positive T cells expressing the p45 Tcf7 isoform and beta-catenin had enhanced Il2 (147680) production capacity and enhanced effector capacity to clear Listeria monocytogenes. Zhao et al. (2010) concluded that constitutive activation of the Wnt pathway favors memory CD8 T-cell formation during immunization, resulting in enhanced immunity upon a second encounter with the same pathogen.
Using a genetic approach, Driessens et al. (2010) found no evidence that the beta-catenin pathway regulates T-cell memory phenotype, in contrast with the findings of Gattinoni et al. (2009). The findings of Driessens et al. (2010) suggested that the generation of Cd8-positive memory stem cells observed by Gattinoni et al. (2009) with the use of Gsk3b inhibitors was not a consequence of activation of the beta-catenin pathway, but was rather due activation of another Gsk3b-dependent pathway. In a reply, Gattinoni et al. (2010) noted that others, including Zhao et al. (2010) and Jeannet et al. (2010), had also identified Wnt and beta-catenin as crucial factors in postthymic Cd8-positive T-cell differentiation and memory development. Using Western blot analysis, Gattinoni et al. (2010) showed that addition of Wnt3a or Gsk3b inhibitor stabilized beta-catenin in primed Cd8-positive mouse T cells.
Weber et al. (2011) found that Tcf7 was highly expressed in mouse early tymic progenitor cells and that its expression was upregulated in response to Notch1 (190198) signals. Forcible expression of human TCF7 in mouse bone marrow progenitors drove development of T-lineage cells in the absence of Notch1 signals. These Tcf7-induced cells expressed T-cell-specific transcription factors, such as Gata3 (131320) and Bcl11b (606558), as well as T-cell receptor components, such as Cd3e. Weber et al. (2011) concluded that TCF7 is essential for normal T-cell development and sufficient to establish many components of T-cell identity.
Verbeek et al. (1995) generated 2 independent germline mutations in Tcf7 by targeted disruption and found that thymocyte development in the otherwise normal mutant mice was blocked at the transition from the Cd8-positive immature single-positive to the Cd4 (186940)-positive/Cd8-positive double-positive stage. In contrast with wildtype mice, most of the immature single-positive cells in the mutant mice were not in the cell cycle, and the number of immunocompetent T cells in the peripheral lymphoid organs was reduced. Verbeek et al. (1995) concluded that TCF7 controls an essential step in thymocyte differentiation.
Roose et al. (1999) found that Tcf7 -/- mice developed adenomas in the gut and mammary glands. They hypothesized that one possible explanation for the tumor phenotype in Tcf7 -/- mice is that Tcf7 acts as a feedback transcriptional repressor of beta-catenin/Tcf4 target genes, and that disruption of this negative-feedback loop allows the formation of epithelial tumors, much like the loss of Apc. This notion predicts synergy between the loss of Tcf7 and of Apc. To test this, Roose et al. (1999) crossed the Apc allele Min into a Tcf7 -/- strain. Min/+ mice developed multiple polyps, mostly in the small intestine. They infrequently developed extraintestinal neoplasia, notably adenoacanthomas in the mammary gland. Min/+ Tcf7 -/- mice displayed a marked enhancement of the intestinal Min/+ phenotype. All intestinal neoplasms expressed high levels of beta-catenin. In addition, all females carried adenoacanthomas of the mammary gland by 8 weeks of age, while substantial numbers of older male mice developed similar lesions. Roose et al. (1999) concluded that TCF7 may act as a feedback repressor of beta-catenin/TCF4 target genes and thus may cooperate with APC to suppress malignant transformation of epithelial cells.
Jeannet et al. (2010) found that mice lacking Tcf7, a nuclear effector of Wnt signaling, mounted normal effector and memory Cd8-positive T-cell responses to viral infection. However, Tcf7-deficient mice were impaired in their ability to expand upon secondary challenge and to protect from recurrent virus infection due to a lack of Cd8 memory precursor T cells. Establishment of memory cells was dependent on the Tcf7 beta-catenin-binding domain and required the Tcf7 coactivators and Wnt signaling intermediates beta-catenin and gamma-catenin (JUP; 173325). Jeannet et al. (2010) concluded that the Wnt signaling pathway plays an essential role for CD8 central memory T-cell differentiation and proposed that modulation of Wnt signaling may be exploited to improve the generation of CD8 memory T cells during vaccination or immunotherapy.
Zhou et al. (2010) showed that loss of Tcf7 in mice limited proliferation of Cd8-positive effector T cells and impaired their differentiation into memory cells. Tcf7 -/- memory Cd8-positive T cells were progressively lost and exhibited reduced expression of Bcl2 (151430) and Il2rb (146710) and diminished Il15 (600554)-driven proliferation. Transcriptome analysis of Tcf7 -/- memory Cd8-positive cells showed strong downregulation of Eomes (604615). The Wnt-Tcf7 pathway was necessary and sufficient for inducing optimal expression of Eomes, which positively regulated Il2rb expression and Il15 responsiveness. Chromatin immunoprecipitation analysis revealed direct and specific binding of Tcf7 and multiple conserved cis-regulatory sequences of the Eomes gene. Zhou et al. (2010) concluded that TCF7 is a critical player in a transcriptional program that regulates memory CD8 differentiation and longevity.
Although the symbol TCF1 (T cell-specific transcription factor-1) is used in the literature for this gene, its official designation is TCF7. It should not be confused with the HNF1A gene (142410), which has also been referred to as TCF1 (transcription factor-1) in the literature.
Driessens, G., Zheng, Y., Gajewski, T. F. Beta-catenin does not regulate memory T cell phenotype. (Letter) Nature Med. 16: 513-514, 2010. [PubMed: 20448567] [Full Text: https://doi.org/10.1038/nm0510-513]
Gattinoni, L., Ji, Y., Restifo, N. P. Reply to Driessens et al. (Letter) Nature Med. 16: 514-515, 2010.
Gattinoni, L., Zhong, X.-S., Palmer, D. C., Ji, Y., Hinrichs, C. S., Yu, Z., Wrzesinski, C., Boni, A., Cassard, L., Garvin, L. M., Paulos, C. M., Muranski, P., Restifo, N. P. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nature Med. 15: 808-813, 2009. [PubMed: 19525962] [Full Text: https://doi.org/10.1038/nm.1982]
Jeannet, G., Boudousquie, C., Gardiol, N., Kang, J., Huelsken, J., Held, W. Essential role of the Wnt pathway effector Tcf-1 for the establishment of functional CD8 T cell memory. Proc. Nat. Acad. Sci. 107: 9777-9782, 2010. [PubMed: 20457902] [Full Text: https://doi.org/10.1073/pnas.0914127107]
Kingsmore, S. F., Watson, M. L., Seldin, M. F. Genetic mapping of the T lymphocyte-specific transcription factor 7 gene on mouse chromosome 11. Mammalian Genome 6: 378 only, 1995. [PubMed: 7626895] [Full Text: https://doi.org/10.1007/BF00364808]
Roose, J., Huls, G., van Beest, M., Moerer, P., van der Horn, K., Goldschmeding, R., Logtenberg, T., Clevers, H. Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1. Science 285: 1923-1926, 1999. [PubMed: 10489374] [Full Text: https://doi.org/10.1126/science.285.5435.1923]
van de Wetering, M., Castrop, J., Korinek, V., Clevers, H. Extensive alternative splicing and dual promoter usage generate Tcf-1 protein isoforms with differential transcription control properties. Molec. Cell. Biol. 16: 745-752, 1996. [PubMed: 8622675] [Full Text: https://doi.org/10.1128/MCB.16.3.745]
van de Wetering, M., Oosterwegel, M., Dooijes, D., Clevers, H. Identification and cloning of TCF-1, a T lymphocyte-specific transcription factor containing a sequence-specific HMG box. EMBO J. 10: 123-132, 1991. [PubMed: 1989880] [Full Text: https://doi.org/10.1002/j.1460-2075.1991.tb07928.x]
van de Wetering, M., Oosterwegel, M., Holstege, F., Dooyes, D., Suijkerbuijk, R., Geurts van Kessel, A., Clevers, H. The human T cell transcription factor-1 gene: structure, localization, and promoter characterization. J. Biol. Chem. 267: 8530-8536, 1992. [PubMed: 1569101]
van de Wetering, M., Suijkerbuijk, R., Geurts van Kessel, A., Clevers, H. Assignment of the human T lymphocyte-specific transcription factor TCF-1 to chromosome 5, band q31.1. (Abstract) Cytogenet. Cell Genet. 58: 1906 only, 1991.
Verbeek, S., Izon, D., Hofhuis, F., Robanus-Maandag, E., te Riele, H., van de Wetering, M., Oosterwegel, M., Wilson, A., MacDonald, H. R., Clevers, H. An HMG-box-containing T-cell factor required for thymocyte differentiation. Nature 374: 70-74, 1995. [PubMed: 7870176] [Full Text: https://doi.org/10.1038/374070a0]
Weber, B. N., Chi, A. W.-S., Chavez, A., Yashiro-Ohtani, Y., Yang, Q., Shestova, O., Bhandoola, A. A critical role for TCF-1 in T-lineage specification and differentiation. Nature 476: 63-68, 2011. [PubMed: 21814277] [Full Text: https://doi.org/10.1038/nature10279]
Zhao, D.-M., Yu, S., Zhou, X., Haring, J. S., Held, W., Badovinac, V. P., Harty, J. T., Xue, H.-H. Constitutive activation of Wnt signaling favors generation of memory CD8 T cells. J. Immun. 184: 1191-1199, 2010. [PubMed: 20026746] [Full Text: https://doi.org/10.4049/jimmunol.0901199]
Zhou, X., Yu, S., Zhao, D.-M., Harty, J. T., Badovinac, V. P., Xue, H.-H. Differentiation and persistence of memory CD8+ T cells depend on T cell factor 1. Immunity 33: 229-240, 2010. [PubMed: 20727791] [Full Text: https://doi.org/10.1016/j.immuni.2010.08.002]