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The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential

Nature Immunology volume 13, pages 412–419 (2012)Cite this article

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Abstract

The stepwise commitment from hematopoietic stem cells in the bone marrow to T lymphocyte–restricted progenitors in the thymus represents a paradigm for understanding the requirement for distinct extrinsic cues during different stages of lineage restriction from multipotent to lineage-restricted progenitors. However, the commitment stage at which progenitors migrate from the bone marrow to the thymus remains unclear. Here we provide functional and molecular evidence at the single-cell level that the earliest progenitors in the neonatal thymus had combined granulocyte-monocyte, T lymphocyte and B lymphocyte lineage potential but not megakaryocyte-erythroid lineage potential. These potentials were identical to those of candidate thymus-seeding progenitors in the bone marrow, which were closely related at the molecular level. Our findings establish the distinct lineage-restriction stage at which the T cell lineage–commitment process transits from the bone marrow to the remote thymus.

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Figure 1: ETPs are multipotent lympho-myeloid restricted progenitors.
Figure 2: ETPs have combined T cell, B cell and GM lineage potential.
Figure 3: Absence of pluripotent HSCs in newborn thymus.
Figure 4: The gene expression of ETPs clusters closer to that of candidate TSPs in the bone marrow than to that of other thymic progenitors.
Figure 5: ETPs, IL-7Rα+ LMPPs and CLPs have closely related T cell– and myeloid-lineage transcriptional profiles.
Figure 6: Expression of genes associated with myeloid and lymphoid cells.

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Acknowledgements

We thank N. Sakaguchi (Kumamoto University) for mice with Rag1-driven GFP expression; T. Graf (Center for Genomic Regulation) for mice with expression of enhanced GFP (eGFP) driven by the gene encoding lysozyme M4; S. Cory (Walter and Eliza Hall Institute of Medical Research) for vavP-Mcl1–trangenic mice; M. Reth (Max Planck Institute of Immunobiology) for Cd79atm1(cre)Reth mice; S. Srinivas (University of Oxford) for mice expressing enhanced yellow fluorescent protein from the Rosa26 locus; A. Cumano (Institut Pasteur) for OP9 and OP9-DL1 stromal cells; Biomedical Services at Oxford University for animal support; S. Clark, T. Furey and B. Wu for technical assistance; and E. Zuo and M. Eckart at the Stanford Protein and Nucleic Acid Facility for gene array services. Supported by the Medical Research Council, UK (H4RPLK0 to S.E.W.J. and EU-FP7 EuroSyStem Integrated projects to S.E.W.J., C.B. and A.F.), Leukaemia and Lymphoma Research (C.B., A.F. and A.J.M.), the Crafoord Foundation (A.H.), The George Danielsson Foundation (A.H.) and Swedish Society for Medicine and Swedish Cancer Foundation (A.H.).

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Author notes

  1. Helen Ferry & Tariq Enver

    Present address: Present addresses: Experimental Medicine Division, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK (H.F.) and University College London Cancer Institute, London, UK (T.E.).,

  2. Tiago C Luis and Hanane Boukarabila: These authors contributed equally to this work.

Authors and Affiliations

  1. Haematopoietic Stem Cell Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK

    Sidinh Luc, Tiago C Luis, Hanane Boukarabila, Iain C Macaulay, Natalija Buza-Vidas, Tiphaine Bouriez-Jones, Michael Lutteropp, Petter S Woll, Stephen J Loughran, Adam J Mead, Takuo Mizukami, Sahoko Matsuoka, Helen Ferry, Sara Duarte, Deborah Atkinson, Aniela Domanski & Sten Eirik W Jacobsen

  2. Hematopoietic Stem Cell Laboratory, Lund Stem Cell Center, Lund University, Lund, Sweden

    Sidinh Luc, Anne Hultquist, Kristina Anderson & Sten Eirik W Jacobsen

  3. Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    Sidinh Luc, Michael Lutteropp, John Brown, Shamit Soneji, Roger Patient, Marella de Bruijn, Tariq Enver & Sten Eirik W Jacobsen

  4. Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK

    Natalija Buza-Vidas, Alison Farley, Alejandra Sanjuan-Pla, Claus Nerlov & Clare Blackburn

  5. European Molecular Biology Laboratory Mouse Biology Unit, Monterotondo, Italy

    Cintia Carella

  6. Institut National de la Santé et de la Recherche Médicale U1009, Villejuif, France

    Isabelle Godin

  7. Institut Gustave Roussy, Villejuif, France

    Isabelle Godin

  8. University of Paris-Sud, Orsay, France

    Isabelle Godin

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Contributions

S.E.W.J. and S.L. designed and conceived of the overall research, analyzed the data and wrote the manuscript, which was subsequently reviewed and approved by all authors; J.B. processed RNA samples; I.C.M. and S.S. analyzed the microarray data; A.J.M., D.A. and A.H. did quantitative and single-cell PCR; A.J.M., S.M. and K.A. did morphology analyses; H.F., S.L. and M.L. sorted cells by flow cytometry; S.L., M.L., T.B.-J., S.D., N.B.-V., H.B., T.C.L., A.D. and S.J.L. contributed to flow cytometry and in vitro culture experiments; S.L., S.D., N.B.-V., P.S.W., T.C.L. and H.B. did in vivo transplantations; T.E. provided assistance in the design and analysis of microarray experiments; C.B., A.F., R.P., M.d.B., I.G. and T.M. contributed advice and input on experimental design; and C.N., A.S.-P. and C.C. generated and provided input on studies of mice expressing eGFP driven by Vwf (encoding the von Willebrand factor homolog).

Corresponding author

Correspondence to Sten Eirik W Jacobsen.

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Luc, S., Luis, T., Boukarabila, H. et al. The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential. Nat Immunol 13, 412–419 (2012). https://doi.org/10.1038/ni.2255

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