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Proc Natl Acad Sci U S A. 2015 Nov 3;112(44):E6020-7. doi: 10.1073/pnas.1519118112. Epub 2015 Oct 19.

Development of a diverse human T-cell repertoire despite stringent restriction of hematopoietic clonality in the thymus.

Author information

1
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2300 RC, The Netherlands; m.h.brugman@lumc.nl vanrood@europdonor.nl F.J.T.Staal@lumc.nl.
2
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2300 RC, The Netherlands;
3
Department of Immunology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands;
4
Department of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Groningen 9713 AV, The Netherlands.

Abstract

The fate and numbers of hematopoietic stem cells (HSC) and their progeny that seed the thymus constitute a fundamental question with important clinical implications. HSC transplantation is often complicated by limited T-cell reconstitution, especially when HSC from umbilical cord blood are used. Attempts to improve immune reconstitution have until now been unsuccessful, underscoring the need for better insight into thymic reconstitution. Here we made use of the NOD-SCID-IL-2Rγ(-/-) xenograft model and lentiviral cellular barcoding of human HSCs to study T-cell development in the thymus at a clonal level. Barcoded HSCs showed robust (>80% human chimerism) and reproducible myeloid and lymphoid engraftment, with T cells arising 12 wk after transplantation. A very limited number of HSC clones (<10) repopulated the xenografted thymus, with further restriction of the number of clones during subsequent development. Nevertheless, T-cell receptor rearrangements were polyclonal and showed a diverse repertoire, demonstrating that a multitude of T-lymphocyte clones can develop from a single HSC clone. Our data imply that intrathymic clonal fitness is important during T-cell development. As a consequence, immune incompetence after HSC transplantation is not related to the transplantation of limited numbers of HSC but to intrathymic events.

KEYWORDS:

T lymphocyte; T-cell development; T-cell receptor; hematopoietic stem cell; thymus

PMID:
26483497
PMCID:
PMC4640754
DOI:
10.1073/pnas.1519118112
[Indexed for MEDLINE]
Free PMC Article

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