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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-11, Vol.112 (44), p.E6020-E6027
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Bone Marrow Cells - cytology; Cloning; Humans; Mice; Mice, Inbred NOD; Mice, SCID; PNAS Plus; Stem cells; T cell receptors; T-Lymphocytes - cytology; Thymus Gland - cytology; Thyroid gland; Transplants & implants; Umbilical cord
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1519118112

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 (