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A critical role for TCF-1 in T-lineage specification and differentiation

Abstract

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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Figure 1: TCF-1 is necessary for early T-lineage development and specification.
Figure 2: Ectopic expression of TCF-1 elicits T-lineage cells in vitro.
Figure 3: TCF-1 upregulates expression of T-lineage specific genes.
Figure 4: TCF-1 is expressed in the earliest T cell progenitors and is downstream of Notch1.

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Primary accessions

Gene Expression Omnibus

Data deposits

Gene expression data have been deposited in the Gene Expression Omnibus database under accession numbers GSE26559 and GSE26560.

References

  1. Schwarz, B. A. et al. Selective thymus settling regulated by cytokine and chemokine receptors. J. Immunol. 178, 2008–2017 (2007)

    Article  CAS  Google Scholar 

  2. 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)

    CAS  PubMed  Google Scholar 

  3. 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)

    Article  CAS  Google Scholar 

  4. Rothenberg, E. V., Zhang, J. & Li, L. Multilayered specification of the T-cell lineage fate. Immunol. Rev. 238, 150–168 (2010)

    Article  CAS  Google Scholar 

  5. Pui, J. C. et al. Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity 11, 299–308 (1999)

    Article  CAS  Google Scholar 

  6. Radtke, F. et al. Deficient T cell fate specification in mice with an induced inactivation of Notch1 . Immunity 10, 547–558 (1999)

    Article  CAS  Google Scholar 

  7. Sambandam, A. et al. Notch signaling controls the generation and differentiation of early T lineage progenitors. Nature Immunol. 6, 663–670 (2005)

    Article  CAS  Google Scholar 

  8. 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)

    Article  CAS  Google Scholar 

  9. Verbeek, S. et al. An HMG-box-containing T-cell factor required for thymocyte differentiation. Nature 374, 70–74 (1995)

    Article  ADS  CAS  Google Scholar 

  10. Schilham, M. W. et al. Critical involvement of Tcf-1 in expansion of thymocytes. J. Immunol. 161, 3984–3991 (1998)

    CAS  PubMed  Google Scholar 

  11. Goux, D. et al. Cooperating pre-T-cell receptor and TCF-1-dependent signals ensure thymocyte survival. Blood 106, 1726–1733 (2005)

    Article  CAS  Google Scholar 

  12. 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)

    Article  CAS  Google Scholar 

  13. Schmitt, T. M. & Zuniga-Pflucker, J. C. T-cell development, doing it in a dish. Immunol. Rev. 209, 95–102 (2006)

    Article  Google Scholar 

  14. 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)

    Article  CAS  Google Scholar 

  15. Cobas, M. et al. β-catenin is dispensable for hematopoiesis and lymphopoiesis. J. Exp. Med. 199, 221–229 (2004)

    Article  CAS  Google Scholar 

  16. Jeannet, G. et al. Long-term, multilineage hematopoiesis occurs in the combined absence of β-catenin and γ-catenin. Blood 111, 142–149 (2008)

    Article  CAS  Google Scholar 

  17. Tago, K. et al. Inhibition of Wnt signaling by ICAT, a novel β-catenin-interacting protein. Genes Dev. 14, 1741–1749 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 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)

    Article  CAS  Google Scholar 

  19. Deftos, M. L. et al. Notch1 signaling promotes the maturation of CD4 and CD8 SP thymocytes. Immunity 13, 73–84 (2000)

    Article  CAS  Google Scholar 

  20. 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)

    Article  CAS  Google Scholar 

  21. 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)

    Article  CAS  Google Scholar 

  22. Hosoya, T. et al. GATA-3 is required for early T lineage progenitor development. J. Exp. Med. 206, 2987–3000 (2009)

    Article  CAS  Google Scholar 

  23. Ikawa, T. et al. An essential developmental checkpoint for production of the T cell lineage. Science 329, 93–96 (2010)

    Article  ADS  CAS  Google Scholar 

  24. 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)

    Article  ADS  CAS  Google Scholar 

  25. Li, P. et al. Reprogramming of T cells to natural killer-like cells upon Bcl11b deletion. Science 329, 85–89 (2010)

    Article  ADS  CAS  Google Scholar 

  26. 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)

    Article  CAS  Google Scholar 

  27. Yashiro-Ohtani, Y. et al. Pre-TCR signaling inactivates Notch1 transcription by antagonizing E2A. Genes Dev. 23, 1665–1676 (2009)

    Article  CAS  Google Scholar 

  28. 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)

    Article  CAS  Google Scholar 

  29. 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)

    Article  CAS  Google Scholar 

  30. Liu, Z. et al. Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice. J. Clin. Invest. 121, 800–808 (2011)

    Article  CAS  Google Scholar 

  31. 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)

    CAS  PubMed  Google Scholar 

  32. 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)

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Knudsen, S. Promoter2.0: for the recognition of PolII promoter sequences. Bioinformatics 15, 356–361 (1999)

    Article  CAS  Google Scholar 

  34. 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)

    Article  CAS  Google Scholar 

  35. Pavlidis, P. & Noble, W. S. Matrix2png: a utility for visualizing matrix data. Bioinformatics 19, 295–296 (2003)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.).

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B.N.W., A.W.-S.C. and A.B. designed and performed the experiments. Q.Y., Y.Y.-O. and A.C. helped with experiments. O.S. provided mice and technical assistance. B.N.W. and A.B. wrote the paper.

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Correspondence to Avinash Bhandoola.

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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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