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Mast cell lineage diversion of T lineage precursors by the essential T cell transcription factor GATA-3

Nature Immunology volume 8, pages 845–855 (2007)Cite this article

Abstract

GATA-3 is essential for T cell development from the earliest stages. However, abundant GATA-3 can drive T lineage precursors to a non–T cell fate, depending on Notch signaling and developmental stage. Here, overexpression of GATA-3 blocked the survival of pro–T cells when Notch-Delta signals were present but enhanced viability in their absence. In fetal thymocytes at the double-negative 1 (DN1) stage and DN2 stage but not those at the DN3 stage, overexpression of GATA-3 rapidly induced respecification to the mast cell lineage with high frequency by direct transcriptional 'reprogramming'. Normal DN2 thymocytes also showed mast cell potential when interleukin 3 and stem cell factor were added in the absence of Notch signaling. Our results suggest a close relationship between the pro–T cell and mast cell programs and a previously unknown function for Notch in T lineage fidelity.

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Figure 1: Inhibition of the T lineage specification of prethymic precursors by forced expression of GATA-3.
Figure 2: GATA-3 overexpression inhibits the differentiation of fetal thymocytes but enhances growth and causes non–T lineage diversion in the absence of Notch-DL1 signaling.
Figure 3: GATA-3 redirects Thy-1+ thymocytes to the mast cell lineage.
Figure 4: Kinetics of thymocyte 'reprogramming' by GATA-3.
Figure 5: Developmental boundaries and frequency of GATA-3-mediated lineage diversion.
Figure 6: Mast cell lineage potential of normal, unmanipulated fetal thymocytes.

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References

  1. Samson, S.I. et al. GATA-3 promotes maturation, IFN-γ production, and liver-specific homing of NK cells. Immunity 19, 701–711 (2003).

    Article  CAS  Google Scholar 

  2. Hendriks, R.W. et al. Expression of the transcription factor GATA-3 is required for the development of the earliest T cell progenitors and correlates with stages of cellular proliferation in the thymus. Eur. J. Immunol. 29, 1912–1918 (1999).

    Article  CAS  Google Scholar 

  3. Ting, C-N., Olson, M.C., Barton, K.P. & Leiden, J.M. Transcription factor GATA-3 is required for development of the T-cell lineage. Nature 384, 474–478 (1996).

    Article  CAS  Google Scholar 

  4. Rothenberg, E.V. & Taghon, T. Molecular genetics of T cell development. Annu. Rev. Immunol. 23, 601–649 (2005).

    Article  CAS  Google Scholar 

  5. Zhu, J., Yamane, H., Cote-Sierra, J., Guo, L. & Paul, W.E. GATA-3 promotes Th2 responses through three different mechanisms: induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors. Cell Res. 16, 3–10 (2006).

    Article  CAS  Google Scholar 

  6. Höflinger, S. et al. Analysis of Notch1 function by in vitro T cell differentiation of Pax5 mutant lymphoid progenitors. J. Immunol. 173, 3935–3944 (2004).

    Article  Google Scholar 

  7. Taghon, T.N., David, E-S., Zúñiga-Pflücker, 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 

  8. Chen, D. & Zhang, G. Enforced expression of the GATA-3 transcription factor affects cell fate decisions in hematopoiesis. Exp. Hematol. 29, 971–980 (2001).

    Article  CAS  Google Scholar 

  9. Taghon, T. et al. Enforced expression of GATA-3 severely reduces human thymic cellularity. J. Immunol. 167, 4468–4475 (2001).

    Article  CAS  Google Scholar 

  10. Nawijn, M.C. et al. Enforced expression of GATA-3 during T cell development inhibits maturation of CD8 single-positive cells and induces thymic lymphoma in transgenic mice. J. Immunol. 167, 715–723 (2001).

    Article  CAS  Google Scholar 

  11. Anderson, M.K. et al. Definition of regulatory network elements for T-cell development by perturbation analysis with PU.1 and GATA-3. Dev. Biol. 246, 103–121 (2002).

    Article  CAS  Google Scholar 

  12. Heavey, B., Charalambous, C., Cobaleda, C. & Busslinger, M. Myeloid lineage switch of Pax5 mutant but not wild-type B cell progenitors by C/EBPα and GATA factors. EMBO J. 22, 3887–3897 (2003).

    Article  CAS  Google Scholar 

  13. Zhu, J. et al. Growth factor independent-1 induced by IL-4 regulates Th2 cell proliferation. Immunity 16, 733–744 (2002).

    Article  CAS  Google Scholar 

  14. Ezoe, S. et al. GATA-2/estrogen receptor chimera regulates cytokine-dependent growth of hematopoietic cells through accumulation of p21WAF1 and p27Kip1 proteins. Blood 100, 3512–3520 (2002).

    Article  CAS  Google Scholar 

  15. Hernández-Hoyos, G., Anderson, M.K., Wang, C., Rothenberg, E.V. & Alberola-Ila, J. GATA-3 expression is controlled by TCR signals and regulates CD4/CD8 differentiation. Immunity 19, 83–94 (2003).

    Article  Google Scholar 

  16. Yamagata, T. et al. Acetylation of GATA-3 affects T-cell survival and homing to secondary lymphoid organs. EMBO J. 19, 4676–4687 (2000).

    Article  CAS  Google Scholar 

  17. Zúñiga-Pflücker, J.C. T-cell development made simple. Nat. Rev. Immunol. 4, 67–72 (2004).

    Article  Google Scholar 

  18. Shortman, K. et al. The linkage between T-cell and dendritic cell development in the mouse thymus. Immunol. Rev. 165, 39–46 (1998).

    Article  CAS  Google Scholar 

  19. Shen, H.Q. et al. T/NK bipotent progenitors in the thymus retain the potential to generate dendritic cells. J. Immunol. 171, 3401–3406 (2003).

    Article  CAS  Google Scholar 

  20. Schmitt, T.M., Ciofani, M., Petrie, H.T. & Zúñiga-Pflücker, J.C. Maintenance of T cell specification and differentiation requires recurrent Notch receptor-ligand interactions. J. Exp. Med. 200, 469–479 (2004).

    Article  CAS  Google Scholar 

  21. Balciunaite, G., Ceredig, R. & Rolink, A.G. The earliest subpopulation of mouse thymocytes contains potent T, significant macrophage, and natural killer cell but no B-lymphocyte potential. Blood 105, 1930–1936 (2005).

    Article  CAS  Google Scholar 

  22. David-Fung, E.S. et al. Progression of regulatory gene expression states in fetal and adult pro-T cell development. Immunol. Rev. 209, 212–236 (2006).

    Article  CAS  Google Scholar 

  23. Taghon, T., Yui, M.A., Pant, R., Diamond, R.A. & Rothenberg, E.V. 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 

  24. Allman, D. et al. Thymopoiesis independent of common lymphoid progenitors. Nat. Immunol. 4, 168–174 (2003).

    Article  CAS  Google Scholar 

  25. Igarashi, H., Gregory, S.C., Yokota, T., Sakaguchi, N. & Kincade, P.W. Transcription from the RAG1 locus marks the earliest lymphocyte progenitors in bone marrow. Immunity 17, 117–130 (2002).

    Article  CAS  Google Scholar 

  26. Tsai, F.Y. & Orkin, S.H. Transcription factor GATA-2 is required for proliferation/survival of early hematopoietic cells and mast cell formation, but not for erythroid and myeloid terminal differentiation. Blood 89, 3636–3643 (1997).

    CAS  PubMed  Google Scholar 

  27. Walsh, J.C. et al. Cooperative and antagonistic interplay between PU.1 and GATA-2 in the specification of myeloid cell fates. Immunity 17, 665–676 (2002).

    Article  CAS  Google Scholar 

  28. Iwasaki, H. et al. The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages. Genes Dev. 20, 3010–3021 (2006).

    Article  CAS  Google Scholar 

  29. Takemoto, N., Arai, K. & Miyatake, S. Cutting edge: the differential involvement of the N-finger of GATA-3 in chromatin remodeling and transactivation during Th2 development. J. Immunol. 169, 4103–4107 (2002).

    Article  CAS  Google Scholar 

  30. Franco, C.B. et al. Notch/Delta signaling constrains re-engineering of pro-T cells by PU.1. Proc. Natl. Acad. Sci. USA 103, 11993–11998 (2006).

    Article  CAS  Google Scholar 

  31. Burnet, F.M. The probable relationship of some or all mast cells to the T-cell system. Cell. Immunol. 30, 358–360 (1977).

    Article  CAS  Google Scholar 

  32. Rodewald, H-R., Dessing, M., Dvorak, A.M. & Galli, S.J. Identification of a committed precursor for the mast cell lineage. Science 271, 818–822 (1996).

    Article  CAS  Google Scholar 

  33. Crivellato, E., Nico, B., Battistig, M., Beltrami, C.A. & Ribatti, D. The thymus is a site of mast cell development in chicken embryos. Anat. Embryol. (Berl.) 209, 243–249 (2005).

    Article  CAS  Google Scholar 

  34. Wise, W.S., Still, W.J. & Joshi, V.V. Severe combined immunodeficiency with thymic mast cell hyperplasia. Arch. Pathol. Lab. Med. 100, 283–286 (1976).

    CAS  PubMed  Google Scholar 

  35. Murphy, M., Friend, D.S., Pike-Nobile, L. & Epstein, L.B. Tumor necrosis factor-α and IFN-γ expression in human thymus. Localization and overexpression in Down syndrome (trisomy 21). J. Immunol. 149, 2506–2512 (1992).

    CAS  PubMed  Google Scholar 

  36. Visan, I., Yuan, J.S., Tan, J.B., Cretegny, K. & Guidos, C.J. Regulation of intrathymic T-cell development by Lunatic Fringe-Notch1 interactions. Immunol. Rev. 209, 76–94 (2006).

    Article  CAS  Google Scholar 

  37. Mohtashami, M. & Zúñiga-Pflücker, J.C. Three-dimensional architecture of the thymus is required to maintain Delta-like expression necessary for inducing T cell development. J. Immunol. 176, 730–734 (2006).

    Article  CAS  Google Scholar 

  38. Arinobu, Y. et al. Developmental checkpoints of the basophil/mast cell lineages in adult murine hematopoiesis. Proc. Natl. Acad. Sci. USA 102, 18105–18110 (2005).

    Article  CAS  Google Scholar 

  39. Babina, M. et al. The transcription factor profile of human mast cells in comparison with monocytes and granulocytes. Cell. Mol. Life Sci. 62, 214–226 (2005).

    Article  CAS  Google Scholar 

  40. Nishiyama, C. et al. GATA-1 is required for expression of FcεRI on mast cells: analysis of mast cells derived from GATA-1 knockdown mouse bone marrow. Int. Immunol. 17, 847–856 (2005).

    Article  CAS  Google Scholar 

  41. Chen, C.C., Grimbaldeston, M.A., Tsai, M., Weissman, I.L. & Galli, S.J. Identification of mast cell progenitors in adult mice. Proc. Natl. Acad. Sci. USA 102, 11408–11413 (2005).

    Article  CAS  Google Scholar 

  42. Iwasaki, H. et al. The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages. Genes Dev. 20, 3010–3021 (2006).

    Article  CAS  Google Scholar 

  43. Laiosa, C.V., Stadtfeld, M. & Graf, T. Determinants of lymphoid-myeloid lineage diversification. Annu. Rev. Immunol. 24, 705–738 (2006).

    Article  CAS  Google Scholar 

  44. Laiosa, C.V., Stadtfeld, M., Xie, H., Andres-Aguayo, L. & : Graf, T. Reprogramming of committed T cell progenitors to macrophages and dendritic cells by C/EBPα and PU.1 transcription factors. Immunity 25, 731–744 (2006).

    Article  CAS  Google Scholar 

  45. Ishiko, E. et al. Notch signals inhibit the development of erythroid/megakaryocytic cells by suppressing GATA-1 activity through the induction of HES1. J. Biol. Chem. 280, 4929–4939 (2005).

    Article  CAS  Google Scholar 

  46. Tomita, K. et al. The bHLH gene Hes1 is essential for expansion of early T cell precursors. Genes Dev. 13, 1203–1210 (1999).

    Article  CAS  Google Scholar 

  47. Nishimura, S. et al. A GATA box in the GATA-1 gene hematopoietic enhancer is a critical element in the network of GATA factors and sites that regulate this gene. Mol. Cell. Biol. 20, 713–723 (2000).

    Article  CAS  Google Scholar 

  48. Grass, J.A. et al. GATA-1-dependent transcriptional repression of GATA-2 via disruption of positive autoregulation and domain-wide chromatin remodeling. Proc. Natl. Acad. Sci. USA 100, 8811–8816 (2003).

    Article  CAS  Google Scholar 

  49. Zhou, M. et al. Friend of GATA-1 represses GATA-3-dependent activity in CD4+ T cells. J. Exp. Med. 194, 1461–1471 (2001).

    Article  CAS  Google Scholar 

  50. Pai, S.Y. et al. Critical roles for transcription factor GATA-3 in thymocyte development. Immunity 19, 863–875 (2003).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S.L. Adams and D. Perez for assistance in cell sorting; A. Arias for generating early results related to this project; M.K. Anderson, C.C. Tydell and E.-S. David-Fung for primers; R. Diamond for cell separation advice and help with sorting; R. Bayon, N. Bouey and L. del Carmen Sandoval for animal care; P. Koen for cytometry support; R. Butler, N. Feng and G. De Smet for technical assistance; and V. Stove and colleagues (Department of Clinical Chemistry, University of Ghent) and K. Swerts (Department of Pediatric Hematology and Oncology, University of Ghent) for cytospins and microscopic analysis. Supported by the Beckman Institute at Caltech (for the Caltech Flow Cytometry/Cell Sorting Facility), the National Institutes of Health (R01 CA98925 and R01 CA90233 to E.V.R.; R01 AI064590 to M.A.Y.) and the action 'Return Grants' of the Belgian Science Policy (T.T.).

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  1. Tom Taghon

    Present address: Present address: Ghent University Hospital, 9000 Ghent, Belgium.,

  2. Tom Taghon and Mary A Yui: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent University, Ghent, 9000, Belgium

    Tom Taghon

  2. Division of Biology, California Institute of Technology, Pasadena, 91125, California, USA

    Tom Taghon, Mary A Yui & Ellen V Rothenberg

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T.T., M.A.Y. and E.V.R. designed the experiments, analyzed data and wrote the manuscript; T.T. and M.A.Y. did the research.

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Correspondence to Ellen V Rothenberg.

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Taghon, T., Yui, M. & Rothenberg, E. Mast cell lineage diversion of T lineage precursors by the essential T cell transcription factor GATA-3. Nat Immunol 8, 845–855 (2007). https://doi.org/10.1038/ni1486

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