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The transcription factor Lyl-1 regulates lymphoid specification and the maintenance of early T lineage progenitors

Nature Immunology volume 13, pages 761–769 (2012)Cite this article

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Abstract

Thymopoiesis depends on the recruitment and expansion of bone marrow–derived progenitor populations; tight regulation of these processes is required for maintenance of the homeostasis of the T lineage. Lyl-1, a transcription factor that regulates hematopoietic progenitors, is expressed in thymocyte progenitors until T cell commitment. Here we demonstrate a requirement for Lyl-1 in lymphoid specification and the maintenance of early T lineage progenitors (ETPs). Lyl-1 deficiency resulted in profound defects in the generation of lymphoid-primed multipotent progenitors (LMPPs), common lymphoid progenitors (CLPs) and ETPs. Lyl-1-deficient ETPs and thymocyte progenitors at the CD4−CD8− double-negative 2 (DN2) stage showed more apoptosis, blocked differentiation and impaired population expansion. We identified Gfi1 as a critical transcriptional target of Lyl-1-mediated lymphopoiesis of T cells. Thus, Lyl-1 is a pivotal component of a transcriptional program that controls the lymphoid specification and maintenance of ETPs.

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Figure 1: Lyl1 dose–dependent generation of LMPPs and ETPs.
Figure 2: Lyl-1 promotes the survival of ETPs and DN2 thymocytes.
Figure 3: Impaired T cell development of Lyl1−/− LMPPs.
Figure 4: In vivo T lineage potential of Lyl1−/− LMPPs after intrathymic transplantation.
Figure 5: Reintroduction of Lyl1 restores the T lineage fate of thymic progenitor cells.
Figure 6: Direct regulation of Gfi1 by Lyl-1.
Figure 7: Lyl-1 controls the thymocyte progenitor pool in part via regulation of Gfi1.

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Acknowledgements

We thank M.K. Brenner for comments on the manuscript; and J.C. Zuniga-Pflücker (University of Toronto) for OP9 cell lines. Supported by US National Institutes of Health (DK58192, DK092883, CA126752, P30 CA125123 and AI007495), the Dan L. Duncan Cancer Center, the UK Medical Research Council, Leukaemia and Lymphoma Research, the Dr. Mildred Scheel Foundation for Cancer Research fellowship (F.Z.) and the Cancer Prevention and Research Institute of Texas (RP101499 to F.Z.).

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Authors and Affiliations

  1. Department of Haematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany

    Fabian Zohren

  2. and Department of Molecular and Human Genetics, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA

    Fabian Zohren, George P Souroullas, Min Luo, Ulrike Gerdemann, Maria R Imperato, Georgi L Lukov & Margaret A Goodell

  3. Centro di Ingegneria Genetica–Biotecnologie Avanzate and European School of Molecular Medicine, University of Naples 'Federico II', Naples, Italy

    Maria R Imperato

  4. University of Cambridge Department of Hematology, Cambridge Institute for Medical Research, Cambridge, UK

    Nicola K Wilson & Berthold Göttgens

  5. Department of Biochemistry, Brigham Young University–Hawaii, Laie, Hawaii, USA

    Georgi L Lukov

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Contributions

F.Z. designed and did most of the experiments, analyzed and interpreted data and wrote the manuscript; G.P.S. and G.L.L. did experiments, provided intellectual input and contributed to the writing of the manuscript; M.R.I., M.L., U.G. and N.K.W. did experiments; B.G. analyzed and interpreted data, provided intellectual input and contributed to the writing of the manuscript; and M.A.G. provided financial support, discussed experimental design, data and interpretation, and wrote the manuscript.

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Correspondence to Margaret A Goodell.

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Zohren, F., Souroullas, G., Luo, M. et al. The transcription factor Lyl-1 regulates lymphoid specification and the maintenance of early T lineage progenitors. Nat Immunol 13, 761–769 (2012). https://doi.org/10.1038/ni.2365

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