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Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors

Nature volume 449, pages 473–477 (2007)Cite this article

Abstract

Lineage commitment and differentiation to a mature cell type are considered to be unidirectional and irreversible processes under physiological conditions1. The commitment of haematopoietic progenitors to the B-cell lineage2,3 and their development to mature B lymphocytes4,5 critically depend on the transcription factor encoded by the paired box gene 5 (Pax5). Here we show that conditional Pax5 deletion in mice allowed mature B cells from peripheral lymphoid organs to dedifferentiate in vivo back to early uncommitted progenitors in the bone marrow, which rescued T lymphopoiesis in the thymus of T-cell-deficient mice. These B-cell-derived T lymphocytes carried not only immunoglobulin heavy- and light-chain gene rearrangements but also participated as functional T cells in immune reactions. Mice lacking Pax5 in mature B cells also developed aggressive lymphomas, which were identified by their gene expression profile as progenitor cell tumours. Hence, the complete loss of Pax5 in late B cells could initiate lymphoma development and uncovered an extraordinary plasticity of mature peripheral B cells despite their advanced differentiation stage.

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Figure 1: Development of aggressive progenitor cell lymphomas on Pax5 loss in B lymphocytes.
Figure 2: T-cell reconstitution by Pax5 -deleted mature B cells in Rag2 –/– mice.
Figure 3: Immunoglobulin gene rearrangements in thymocytes of reconstituted Rag2 –/– mice.
Figure 4: Normal immune function of B-cell-derived T cells.

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Acknowledgements

We thank A. Schebesta for cDNA microarray analysis, M. Murphy and F. Alt for spectral karyotype analysis of tumour cells, F. Alt for providing immunoglobulin gene probes, A. Rolink for suggesting the Tcra–/– mouse reconstitution experiment, K. Rajewsky, J. Adams and W. Ellmeier for providing transgenic mouse strains, G. Stengl for FACS sorting, S. Höflinger for help with the V(D)J recombination analysis, and I. Botto and M. Madalinsky for anti-IL-7Rα antibody purification. This research was supported by Boehringer Ingelheim (M.B.), the Austrian Industrial Research Promotion Fund (M.B.), a Spanish ‘Ramon y Cajal’ investigator grant (C.C.), the Fondo de Investigaciónes Sanitarias (C.C.), the Junta de Castilla y León (C.C.) and the Fundación de Investigación MMA (C.C.).

Author Contributions C.C. carried out almost all experimental work and contributed to manuscript writing. W.J. performed the histological analyses and evaluation of the tumours. M.B. contributed to the project planning and wrote the manuscript.

All microarray data have been deposited in the GEO repository at NCBI under accession numbers GSM210098, GSM210099, GSM210100, GSM210101, GSM215734, GSM215735 and GSM213736.

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  1. César Cobaleda

    Present address: Present address: Universidad de Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain.,

Authors and Affiliations

  1. Research Institute of Molecular Pathology, Vienna Biocenter, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria,

    César Cobaleda & Meinrad Busslinger

  2. Department of Pathology, University Hospital, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland,

    Wolfram Jochum

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Correspondence to Meinrad Busslinger.

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Cobaleda, C., Jochum, W. & Busslinger, M. Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors. Nature 449, 473–477 (2007). https://doi.org/10.1038/nature06159

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