Céline La, Aurélie Detavernier, Maria Papadopoulou, Guillem Sanchez Sanchez, Vincent Martens, Séverine Thomas, Muriel Nguyen, Valérie Acolty, Maxime Melchior, Desiree Venturoli, Bérengère de de Toeuf, Abdulkader Azouz, Moosa Rezwani, Yohannes Tafesse, Isoline Verdebout, Anthony Rongvaux, Lena Boehme, Tom Taghon, Koen Venken, Dirk Elewaut, Stanislas Goriely, David Vermijlen
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 scid Il2rγ −/− Kit W41/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.