THE GENERATION OF HUMAN GAMMA-DELTA T-CELL REPERTOIRES DURING FETAL DEVELOPMENT

The nature of how human gamma delta T cells are normally generated is not clear. We have used an RT-PCR assay and DNA sequencing to identify and compare delta-encoded TCRs (TCRDs) that are generated de novo in the fetal gut, liver, and thymus and to determine when, where, and how the TCRD repertoire is established during normal embryonic developmen t. Rearranged TCRDV genes are first expressed outside of the thymus in the liver and primitive gut between 6 and 9 wk gestation. Although DV 1Rs and/or DV2Rs predominated, differences in the pattern of TCRDV gen e rearrangement and transcription in each tissue during ontogeny were identified. Specific, DV2-encoded TCRs are highly conserved throughout ontogeny in the tissues from the same and between genetically distinc t donors. Although the thymic and intestinal gamma delta T cell repert oires partially overlap early in development, they diverge and become nonoverlapping during the second trimester, and the generation of the intestinal gamma delta T cell repertoire is characterized by differenc es in the processing of DV1Rs and DV2Rs. Whereas the structural divers ity of DV1Rs progressively increases during gut development up to birt h, DV2Rs have limited structural diversity throughout ontogeny, Togeth er, our findings provide evidence for the ability of different fetal t issues to support the development of gamma delta T cells.