Cell reports · 2026
In vivo modeling of human γδ T cell ontogeny reveals terminal deoxynucleotidyl transferase as a key regulator of type 3 Vδ2 T cell development.
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La Céline, Detavernier Aurélie, Papadopoulou Maria, Sanchez Sanchez Guillem, Martens Vincent, Thomas Séverine, Nguyen Muriel, Acolty Valérie, Melchior Maxime, Venturoli Desiree, de Toeuf Bérengère, Azouz Abdulkader, Rezwani Moosa, Tafesse Yohannes, Verdebout Isoline, Rongvaux Anthony, Boehme Lena, Taghon Tom, Venken Koen, Elewaut Dirk, Goriely Stanislas, Vermijlen David
Аннотация
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.PrkdcscidIl2rγ-/-KitW41/W41) mice reconstituted with human fetal liver CD34+ 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.