期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：6
页码：E556-E565
DOI：10.1073/pnas.1412058112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceDespite their enormous potential for diversity (in excess of 1015 theoretical receptor specificities), the human {gamma}{delta} T-cell repertoire is dominated by a specific subset expressing the T-cell receptor containing the {gamma}-chain variable region 9 and the {delta}-chain variable region 2 (V{gamma}9V{delta}2) known to react to a set of pathogen-derived small molecules (phosphoantigens). Overrepresentation of this restricted set of {gamma}{delta} T cells in adults has been thought to reflect an antigen-specific selection process resulting from postnatal exposure to pathogens. However, we demonstrate here that restricted V{gamma}9V{delta}2 cells with preprogrammed effector function represent the predominant {gamma}{delta} T-cell subset circulating in human fetal blood. This observation suggests that, despite developing in a sterile environment, the human fetal {gamma}{delta} T cell repertoire is enriched for pathogen-reactive T cells well before pathogen exposure. {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 {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 complementary-determining region 3 (CDR3) in response to encounters with microbes, 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} and 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.
