The vertebrate thymus provides an inductive environment for T-cell development. Within the mouse thymus, Notch signals are indispensable for imposing the T-cell fate on multipotential haematopoietic progenitors, but the downstream effectors that impart T-lineage specification and commitment are not well understood. Here we show that a transcription factor, T-cell factor 1 (TCF-1; also known as transcription factor 7, T-cell specific, TCF7), is a critical regulator in T-cell specification. TCF-1 is highly expressed in the earliest thymic progenitors, and its expression is upregulated by Notch signals. Most importantly, when TCF-1 is forcibly expressed in bone marrow (BM) progenitors, it drives the development of T-lineage cells in the absence of T-inductive Notch1 signals. Further characterization of these TCF-1-induced cells revealed expression of many T-lineage genes, including T-cell-specific transcription factors Gata3 and Bcl11b, and components of the T-cell receptor. Our data suggest a model where Notch signals induce TCF-1, and TCF-1 in turn imprints the T-cell fate by upregulating expression of T-cell essential genes.
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Schwarz, B. A. et al. Selective thymus settling regulated by cytokine and chemokine receptors. J. Immunol. 178, 2008–2017 (2007)
Spangrude, G. J. & Scollay, R. Differentiation of hematopoietic stem cells in irradiated mouse thymic lobes. Kinetics and phenotype of progeny. J. Immunol. 145, 3661–3668 (1990)
Doulatov, S. et al. Revised map of the human progenitor hierarchy shows the origin of macrophages and dendritic cells in early lymphoid development. Nature Immunol. 11, 585–593 (2010)
Rothenberg, E. V., Zhang, J. & Li, L. Multilayered specification of the T-cell lineage fate. Immunol. Rev. 238, 150–168 (2010)
Pui, J. C. et al. Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity 11, 299–308 (1999)
Radtke, F. et al. Deficient T cell fate specification in mice with an induced inactivation of Notch1 . Immunity 10, 547–558 (1999)
Sambandam, A. et al. Notch signaling controls the generation and differentiation of early T lineage progenitors. Nature Immunol. 6, 663–670 (2005)
Taghon, T. N., David, E. S., Zuniga-Pflucker, J. C. & Rothenberg, E. V. Delayed, asynchronous, and reversible T-lineage specification induced by Notch/Delta signaling. Genes Dev. 19, 965–978 (2005)
Verbeek, S. et al. An HMG-box-containing T-cell factor required for thymocyte differentiation. Nature 374, 70–74 (1995)
Schilham, M. W. et al. Critical involvement of Tcf-1 in expansion of thymocytes. J. Immunol. 161, 3984–3991 (1998)
Goux, D. et al. Cooperating pre-T-cell receptor and TCF-1-dependent signals ensure thymocyte survival. Blood 106, 1726–1733 (2005)
Okamura, R. M. et al. Redundant regulation of T cell differentiation and TCRα gene expression by the transcription factors LEF-1 and TCF-1. Immunity 8, 11–20 (1998)
Schmitt, T. M. & Zuniga-Pflucker, J. C. T-cell development, doing it in a dish. Immunol. Rev. 209, 95–102 (2006)
Huang, J. et al. Propensity of adult lymphoid progenitors to progress to DN2/3 stage thymocytes with Notch receptor ligation. J. Immunol. 175, 4858–4865 (2005)
Cobas, M. et al. β-catenin is dispensable for hematopoiesis and lymphopoiesis. J. Exp. Med. 199, 221–229 (2004)
Jeannet, G. et al. Long-term, multilineage hematopoiesis occurs in the combined absence of β-catenin and γ-catenin. Blood 111, 142–149 (2008)
Tago, K. et al. Inhibition of Wnt signaling by ICAT, a novel β-catenin-interacting protein. Genes Dev. 14, 1741–1749 (2000)
Pear, W. S. et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J. Exp. Med. 183, 2283–2291 (1996)
Deftos, M. L. et al. Notch1 signaling promotes the maturation of CD4 and CD8 SP thymocytes. Immunity 13, 73–84 (2000)
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)
Yu, Q. et al. T cell factor 1 initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-γ. Nature Immunol. 10, 992–999 (2009)
Hosoya, T. et al. GATA-3 is required for early T lineage progenitor development. J. Exp. Med. 206, 2987–3000 (2009)
Ikawa, T. et al. An essential developmental checkpoint for production of the T cell lineage. Science 329, 93–96 (2010)
Li, L., Leid, M. & Rothenberg, E. V. An early T cell lineage commitment checkpoint dependent on the transcription factor Bcl11b . Science 329, 89–93 (2010)
Li, P. et al. Reprogramming of T cells to natural killer-like cells upon Bcl11b deletion. Science 329, 85–89 (2010)
Taghon, T. et al. Developmental and molecular characterization of emerging β- and γδ-selected pre-T cells in the adult mouse thymus. Immunity 24, 53–64 (2006)
Yashiro-Ohtani, Y. et al. Pre-TCR signaling inactivates Notch1 transcription by antagonizing E2A. Genes Dev. 23, 1665–1676 (2009)
Lin, Y. C. et al. A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate. Nature Immunol. 11, 635–643 (2010)
Wendorff, A. A. et al. Hes1 is a critical but context-dependent mediator of canonical Notch signaling in lymphocyte development and transformation. Immunity 33, 671–684 (2010)
Liu, Z. et al. Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice. J. Clin. Invest. 121, 800–808 (2011)
Brault, V. et al. Inactivation of the β-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development. Development 128, 1253–1264 (2001)
Huang, J. et al. Pivotal role for glycogen synthase kinase-3 in hematopoietic stem cell homeostasis in mice. J. Clin. Invest. 119, 3519–3529 (2009)
Knudsen, S. Promoter2.0: for the recognition of PolII promoter sequences. Bioinformatics 15, 356–361 (1999)
Weng, A. P. et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 20, 2096–2109 (2006)
Pavlidis, P. & Noble, W. S. Matrix2png: a utility for visualizing matrix data. Bioinformatics 19, 295–296 (2003)
We thank H. Clevers for permission to use TCF-1−/− mice and W. Pear, S. Reiner, C. Bassing, R. Sen and W. Bailis for critical comments. This work was supported by NIH grant AI059621 and a Scholar Award from the Leukemia and Lymphoma Society (A.B.), and institutional training grants T32AI055428 (B.N.W.) and T32CA09140 (A.W.-S.C.).
The authors declare no competing financial interests.
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Weber, B., Chi, AS., Chavez, A. et al. A critical role for TCF-1 in T-lineage specification and differentiation. Nature 476, 63–68 (2011). https://doi.org/10.1038/nature10279
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