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  • Original Article
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Differentiation

Notch induces human T-cell receptor γδ+ thymocytes to differentiate along a parallel, highly proliferative and bipotent CD4 CD8 double-positive pathway

Leukemia volume 26, pages 127–138 (2012)Cite this article

Abstract

In wild-type mice, T-cell receptor (TCR) γδ+ cells differentiate along a CD4 CD8 double-negative (DN) pathway whereas TCRαβ+ cells differentiate along the double-positive (DP) pathway. In the human postnatal thymus (PNT), DN, DP and single-positive (SP) TCRγδ+ populations are present. Here, the precursor–progeny relationship of the various PNT TCRγδ+ populations was studied and the role of the DP TCRγδ+ population during T-cell differentiation was elucidated. We demonstrate that human TCRγδ+ cells differentiate along two pathways downstream from an immature CD1+ DN TCRγδ+ precursor: a Notch-independent DN pathway generating mature DN and CD8αα SP TCRγδ+ cells, and a Notch-dependent, highly proliferative DP pathway generating immature CD4 SP and subsequently DP TCRγδ+ populations. DP TCRγδ+ cells are actively rearranging the TCRα locus, and differentiate to TCR− DP cells, to CD8αβ SP TCRγδ+ cells and to TCRαβ+ cells. Finally, we show that the γδ subset of T-cell acute lymphoblastic leukemias (T-ALL) consists mainly of CD4 SP or DP phenotypes carrying significantly more activating Notch mutations than DN T-ALL. The latter suggests that activating Notch mutations in TCRγδ+ thymocytes induce proliferation and differentiation along the DP pathway in vivo.

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Acknowledgements

We are indebted to Christian De Boever for performing art work. We also thank Dr I Vanhaute (Red Cross Flanders, Oost-Vlaanderen, Belgium), Dr K Francois and Dr G Van Nooten (UZ Ghent, Belgium) for providing human blood samples and PNT, and Dr Tom Boterberg for the irradiation procedures. This work was supported by the Fund for Scientific Research, Flanders (Fonds voor Wetenschappelijk Onderzoek Vlaanderen, FWO) and its Odysseus research program, Stichting tegen Kanker, the geconcerteerde onderzoeksactiviteiten (GOA of the Ghent University) and the Interuniversity Attraction Poles Program (IUAP) supported by the Belgian Science Policy. SVC, SV and GV are supported by the Instituut voor de Aanmoediging van Innovatie door Wetenschap en Technologie in Vlaanderen, IWT; SS, TT and TK are supported by the FWO Vlaanderen.

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Authors and Affiliations

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

    S Van Coppernolle, S Vanhee, G Verstichel, S Snauwaert, I Velghe, M Sinnesael, T Taghon, G Leclercq, J Plum, T Kerre & B Vandekerckhove

  2. Department of Immunology, Erasmus MC, Rotterdam, The Netherlands

    A van der Spek & A W Langerak

  3. Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

    M H Heemskerk

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  1. S Van Coppernolle
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Correspondence to B Vandekerckhove.

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Van Coppernolle, S., Vanhee, S., Verstichel, G. et al. Notch induces human T-cell receptor γδ+ thymocytes to differentiate along a parallel, highly proliferative and bipotent CD4 CD8 double-positive pathway. Leukemia 26, 127–138 (2012). https://doi.org/10.1038/leu.2011.324

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