TCR Sequencing Reveals the Distinct Development of Fetal and Adult Human Vγ9Vδ2 T Cells

Phosphoantigen-reactive V gamma 9V delta 2 T cells represent the main innate human gamma delta T cell subset and dominate the fetal and adult peripheral blood gamma delta T cell repertoire. It has been hypothesized that adult blood V gamma 9V delta 2 T cells find their origin in the fetus like it is established for mouse innate gamma delta T cells. To address this issue, we analyzed the CDR3 of the TCR of human blood and thymic V gamma 9V delta 2 T cells from fetal until adult life. We first identified key differences in the CDR3 repertoire of fetal and adult blood V gamma 9V delta 2 T cells, including in CDR3 features important for phosphoantigen reactivity. Next, we showed that most of these key adult CDR3 features were already present in the postnatal thymus and were further enhanced upon selection in vitro by the microbial-derived phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate. Finally, we demonstrated that the generation of a fetal-type or adult-type V gamma 9V delta 2 CDR3 repertoire is determined by the fetal and postnatal nature of the hematopoietic stem and precursor cell. Thus, our data indicate that fetal blood V gamma 9V delta 2 T cells find their origin in the fetal thymus whereas adult blood V gamma 9V delta 2 T cells are generated to a large degree independently after birth.