In vivo modeling of human γδ T cell ontogeny reveals terminal deoxynucleotidyl transferase as a key regulator of type 3 Vδ2 T cell development
Profound differences in T cell receptor (TCR) repertoire and functional profiles between human and murine γδ T cells pose significant challenges for translational γδ T cell research. Therefore, we generated humanized immune system (HIS) NBSGW (NOD,B6.Prkdc<sup>scid</sup>Il2rγ<sup>-/-</sup>Kit<sup>W41/W41</sup>) mice reconstituted with human fetal liver CD34<sup>+</sup> hematopoietic stem and progenitor cells (HSPCs) enabling evaluation of human γδ T cells in vivo. The HIS mice accurately recapitulate the TCR-associated thymic programming of human γδ T cells-alongside αβ T cell development-and their peripheral effector functions, including the generation of phosphoantigen-reactive Vγ9Vδ2 T cells uniquely found in humans. Moreover, terminal deoxynucleotidyl transferase (TdT) is identified as a key regulator of type 3 Vδ2 T cell development. These findings demonstrate that HIS mice are a powerful model to screen human γδ T cell-targeting immunotherapies and to obtain mechanistic insights into human γδ T cell biology.
Authors
- Tom Taghon (ORCID: https://orcid.org/0000-0002-5781-0288)
- Muriel Nguyen
- Moosa Rezwani (ORCID: https://orcid.org/0000-0001-6325-4444)
- Yohannes Tafesse (ORCID: https://orcid.org/0000-0003-3883-6244)
- Maxime Melchior
- Lena Boehme (ORCID: https://orcid.org/0000-0001-7593-7533)
- Isoline Verdebout (ORCID: https://orcid.org/0000-0002-4012-170X)
- Stanislas Goriely (ORCID: https://orcid.org/0000-0002-7005-6195)
- Aurélie Detavernier (ORCID: https://orcid.org/0009-0000-4732-1854)
- Valérie Acolty (ORCID: https://orcid.org/0000-0002-5681-1246)
- Abdulkader Azouz (ORCID: https://orcid.org/0000-0001-8626-4370)
- Séverine Thomas (ORCID: https://orcid.org/0000-0002-3063-2821)
- Vincent Martens
- Desiree Venturoli
- David Vermijlen
- Maria Papadopoulou
- Koen Venken
- Dirk Elewaut
- Guillem Sanchez Sanchez
- Bérengère de Toeuf
- Céline La
Institutions
- Université Libre de Bruxelles (BE)
- Ghent University (BE)
- Fred Hutch Cancer Center (US)
- Cancer Research Institute Ghent (BE)
- Interuniversity Institute for High Energies (BE)
- VIB-UGent Center for Inflammation Research (BE)
- Walloon Excellence in Lifesciences and Biotechnology (BE)
Publication Details
- Journal
- Cell Reports
- Published
- 2026-02-01
- DOI
- https://doi.org/10.1016/j.celrep.2026.116977
- Citations
- 1
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 24.43