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In vivo modeling of human γδ T cell ontogeny reveals terminal deoxynucleotidyl transferase as a key regulator of type 3 Vδ2 T cell development.

par La, Celine ;Detavernier, Aurélie ;Papadopoulou, Maria ;Sánchez Sánchez, 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, K.;Elewaut, Dirk;Goriely, Stanislas ;Vermijlen, David
Référence Cell Reports, 45, 2, page (116977)
Publication Publié, 2026-02-01

Article révisé par les pairs

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Résumé :

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.