EXTRATHYMIC ORIGIN OF HUMAN GAMMA-DELTA T-CELLS DURING FETAL DEVELOPMENT

We have identified the first TCRs to be generated in vivo during norma l human fetal development. Before thymic formation, the liver is a sit e of generation for a subset of V gamma 9/V delta 2(+) gamma delta T c ells. Analysis of the expression of the male-specific gene, SRY, by V gamma 9/V delta 2(+) gamma delta T cells isolated from the fetal liver of male donors has shown that these cells are generated de novo in th e liver. Examination of TCR-V gamma and -V delta gene expression demon strated that although multiple receptor rearrangements could be detect ed, V gamma 9-JP- and V delta 2-D delta 3-J delta 1/3-encoded receptor s were preferentially expressed in each of five individual liver sampl es. Structural analysis of these receptor chains and those expressed b y a panel of V gamma 9/V delta 2(+) fetal T cell clones showed that th e V gamma 9-JP receptors were invariant or canonical and that the S-ch ains contained non-germ line-encoded structural motifs. gamma delta T cells expressing these structurally limited receptor chains were shown to be functional and capable of responding to mycobacterial Ags. Toge ther with the observation that V gamma 9/V delta 2(+) cells represente d the majority of T cells present in the fetal liver between 7 and 11 wk of development, our findings demonstrate that this subset of gamma delta T cells is a major, and presumably important, component of the h uman fetal immune system.