Development of a diverse human T-cell repertoire despite stringent restriction of hematopoietic clonality in the thymus.
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.
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.
Martijn H
MH
Brugman
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2300 RC, The Netherlands;
Anna-Sophia
AS
Wiekmeijer
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2300 RC, The Netherlands;
Marja
M
van Eggermond
Department of Immunology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands;
Ingrid
I
Wolvers-Tettero
Department of Immunology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands;
Anton W
AW
Langerak
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2300 RC, The Netherlands;
Edwin F E
EF
de Haas
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.
Leonid V
LV
Bystrykh
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.
Jon J
JJ
van Rood
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.
Gerald
G
de Haan
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2300 RC, The Netherlands;
Willem E
WE
Fibbe
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.
Frank J T
FJ
Staal
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013601:T-Lymphocytes / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology*
T lymphocyte; T-cell development; T-cell receptor; hematopoietic stem cell; thymus