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

Martijn H. Brugman; Anna-Sophia Wiekmeijer; Marja van Eggermond; Ingrid Wolvers-Tettero; Anton W. Langerak; Edwin F. E. de Haas; Leonid V. Bystrykh; Jon J. van Rood; Gerald de Haan; Willem E. Fibbe; Frank J. T. Staal

doi:10.1073/pnas.1519118112

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

Martijn H. Brugman, Anna-Sophia Wiekmeijer, Marja van Eggermond, Ingrid Wolvers-Tettero, Anton W. Langerak, Edwin F. E. de Haas, Leonid V. Bystrykh, Jon J. van Rood^*, Gerald de Haan, Willem E. Fibbe, Frank J. T. Staal

^*Corresponding author for this work

Stem Cell Aging Leukemia and Lymphoma (SALL)

Research output: Contribution to journal › Article › Academic › peer-review

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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-2R gamma(-/-) 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 (

Original language	English
Pages (from-to)	E6020-E6027
Number of pages	8
Journal	Proceedings of the National Academy of Science of the United States of America
Volume	112
Issue number	44
DOIs	https://doi.org/10.1073/pnas.1519118112
Publication status	Published - 3-Nov-2015

Keywords

thymus
T-cell receptor
hematopoietic stem cell
T-cell development
T lymphocyte
NONINHERITED MATERNAL ANTIGENS
UMBILICAL-CORD BLOOD
IMMUNE RECONSTITUTION
STEM-CELLS
TRANSPLANTATION
MICE
THYMOPOIESIS
DYNAMICS
GROWTH
QUANTIFICATION

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PNAS-2015-Brugman-E6020-7Final publisher's version, 1.55 MB

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Brugman, M. H., Wiekmeijer, A-S., van Eggermond, M., Wolvers-Tettero, I., Langerak, A. W., de Haas, E. F. E., Bystrykh, L. V., van Rood, J. J., de Haan, G., Fibbe, W. E., & Staal, F. J. T. (2015). Development of a diverse human T-cell repertoire despite stringent restriction of hematopoietic clonality in the thymus. Proceedings of the National Academy of Science of the United States of America, 112(44), E6020-E6027. https://doi.org/10.1073/pnas.1519118112

Brugman, Martijn H. ; Wiekmeijer, Anna-Sophia ; van Eggermond, Marja ; Wolvers-Tettero, Ingrid ; Langerak, Anton W. ; de Haas, Edwin F. E. ; Bystrykh, Leonid V. ; van Rood, Jon J. ; de Haan, Gerald ; Fibbe, Willem E. ; Staal, Frank J. T. / Development of a diverse human T-cell repertoire despite stringent restriction of hematopoietic clonality in the thymus. In: Proceedings of the National Academy of Science of the United States of America. 2015 ; Vol. 112, No. 44. pp. E6020-E6027.

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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-2R gamma(-/-) 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 (",

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doi = "10.1073/pnas.1519118112",

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Brugman, MH, Wiekmeijer, A-S, van Eggermond, M, Wolvers-Tettero, I, Langerak, AW, de Haas, EFE, Bystrykh, LV, van Rood, JJ, de Haan, G, Fibbe, WE & Staal, FJT 2015, 'Development of a diverse human T-cell repertoire despite stringent restriction of hematopoietic clonality in the thymus', Proceedings of the National Academy of Science of the United States of America, vol. 112, no. 44, pp. E6020-E6027. https://doi.org/10.1073/pnas.1519118112

Development of a diverse human T-cell repertoire despite stringent restriction of hematopoietic clonality in the thymus. / Brugman, Martijn H.; Wiekmeijer, Anna-Sophia; van Eggermond, Marja; Wolvers-Tettero, Ingrid; Langerak, Anton W.; de Haas, Edwin F. E.; Bystrykh, Leonid V.; van Rood, Jon J.; de Haan, Gerald; Fibbe, Willem E.; Staal, Frank J. T.

In: Proceedings of the National Academy of Science of the United States of America, Vol. 112, No. 44, 03.11.2015, p. E6020-E6027.

Research output: Contribution to journal › Article › Academic › peer-review

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AU - Wolvers-Tettero, Ingrid

AU - Langerak, Anton W.

AU - de Haas, Edwin F. E.

AU - Bystrykh, Leonid V.

AU - van Rood, Jon J.

AU - de Haan, Gerald

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AU - Staal, Frank J. T.

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AB - 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-2R gamma(-/-) 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 (

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KW - T-cell receptor

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KW - UMBILICAL-CORD BLOOD

KW - IMMUNE RECONSTITUTION

KW - STEM-CELLS

KW - TRANSPLANTATION

KW - MICE

KW - THYMOPOIESIS

KW - DYNAMICS

KW - GROWTH

KW - QUANTIFICATION

U2 - 10.1073/pnas.1519118112

DO - 10.1073/pnas.1519118112

M3 - Article

VL - 112

SP - E6020-E6027

JO - Proceedings of the National Academy of Science of the United States of America

JF - Proceedings of the National Academy of Science of the United States of America

SN - 0027-8424

IS - 44

ER -