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

MH (Martijn) Brugman, AS Wiekmeijer, M van Eggermond, Ingrid Tettero, Ton Langerak, EFE Haas, LV Bystrykh, JJ van Rood, G de Haan, WE Fibbe, Frank Staal

Research output: Contribution to journalArticleAcademicpeer-review

23 Citations (Scopus)

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 (<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.
Original languageUndefined/Unknown
Pages (from-to)E6020-E6027
JournalProceedings of the National Academy of Sciences of the United States of Ame
Volume112
Issue number44
DOIs
Publication statusPublished - 2015

Cite this