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

Research output: Contribution to journalArticleAcademicpeer-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 languageEnglish
Pages (from-to)E6020-E6027
Number of pages8
JournalProceedings of the National Academy of Science of the United States of America
Volume112
Issue number44
DOIs
Publication statusPublished - 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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