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

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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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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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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