Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

gamma delta T cells are unconventional T cells recognizing antigens via their gamma delta T-cell receptor (TCR) in a way that is fundamentally different from conventional alpha beta T cells gamma delta T cells usually are divided into subsets according the type of V-gamma and/or V-delta chain they express in their TCR. T cells expressing the TCR containing the gamma-chain variable region 9 and the delta-chain variable region 2 (V gamma 9V delta 2 T cells) are the predominant gamma delta T-cell subset in human adult peripheral blood. The current thought is that this predominance is the result of the postnatal expansion of cells expressing particular complementarydetermining region 3 (CDR3) in response to encounterswithmicrobes, especially those generating phosphoantigens derived from the 2-C-methyl- D-erythritol 4-phosphate pathway of isoprenoid synthesis. However, here we show that, rather than requiring postnatal microbial exposure, V gamma 9V delta 2 T cells are the predominant blood subset in the second-trimester fetus, whereas V delta 1(+) and V delta 3(+) gamma delta T cells are present only at low frequencies at this gestational time. Fetal blood V gamma 9V delta 2 T cells are phosphoantigen responsive and display very limited diversity in the CDR3 of the V gamma 9 chain gene, where a germline- encoded sequence accounts for >50% of all sequences, in association with a prototypic CDR3 delta 2. Furthermore, these fetal blood V gamma 9V delta 2 T cells are functionally preprogrammed (e.g., IFN-gamma nd granzymes-A/K), with properties of rapidly activatable innatelike T cells. Thus, enrichment for phosphoantigen-responsive effector T cells has occurred within the fetus before postnatal microbial exposure. These various characteristics have been linked in the mouse to the action of selecting elements and would establish a much stronger parallel between human and murine gamma delta T cells than is usually articulated.