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.PrkdcscidIl2rγ-/-KitW41/W41) mice reconstituted with human fetal liver CD34+ hematopoietic stem and progenitor cells (HSPCs) enabling human γδ T cells evaluation in vivo. The HIS mice accurately recapitulated the TCR-associated thymic programming of human γδ T cells—alongside αβ T cells—and their peripheral effector functions, including the generation of phosphoantigen-reactive Vγ9Vδ2 T cells uniquely found in humans. Moreover, terminal deoxynucleotidyl transferase (TdT) was 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 in human γδ T cell biology.