Dimova Tanya, Brouwer Margreet, Gosselin Françoise, Tassignon Joël, Leo Oberdan, Donner Catherine, Marchant Arnaud, Vermijlen David
Institute for Medical Immunology, Université Libre de Bruxelles (ULB), 6041 Gosselies, Belgium;
Department of Obstetrics and Gynecology, Hôpital Erasme, 1070 Brussels, Belgium;
Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):E556-65. doi: 10.1073/pnas.1412058112. Epub 2015 Jan 23.
γδ T cells are unconventional T cells recognizing antigens via their γδ T-cell receptor (TCR) in a way that is fundamentally different from conventional αβ T cells. γδ T cells usually are divided into subsets according the type of Vγ and/or Vδ chain they express in their TCR. T cells expressing the TCR containing the γ-chain variable region 9 and the δ-chain variable region 2 (Vγ9Vδ2 T cells) are the predominant γδ 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, Vγ9Vδ2 T cells are the predominant blood subset in the second-trimester fetus, whereas Vδ1(+) and Vδ3(+) γδ T cells are present only at low frequencies at this gestational time. Fetal blood Vγ9Vδ2 T cells are phosphoantigen responsive and display very limited diversity in the CDR3 of the Vγ9 chain gene, where a germline-encoded sequence accounts for >50% of all sequences, in association with a prototypic CDR3δ2. Furthermore, these fetal blood Vγ9Vδ2 T cells are functionally preprogrammed (e.g., IFN-γ 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 γδ T cells than is usually articulated.
γδ T细胞是非常规T细胞，它们通过其γδ T细胞受体（TCR）识别抗原，其方式与常规αβ T细胞有根本不同。γδ T细胞通常根据它们在TCR中表达的Vγ和/或Vδ链的类型分为不同亚群。表达含有γ链可变区9和δ链可变区2的TCR的T细胞（Vγ9Vδ2 T细胞）是成人外周血中主要的γδ T细胞亚群。目前的观点认为，这种优势是表达特定互补决定区3（CDR3）的细胞在出生后因接触微生物，尤其是那些产生源自类异戊二烯合成的2-C-甲基-D-赤藓糖醇4-磷酸途径的磷酸抗原而扩增的结果。然而，我们在此表明，Vγ9Vδ2 T细胞并非需要出生后接触微生物，而是妊娠中期胎儿血液中的主要亚群，而Vδ1(+)和Vδ3(+)γδ T细胞在此孕期仅以低频率存在。胎儿血液中的Vγ9Vδ2 T细胞对磷酸抗原产生反应，并且在Vγ9链基因的CDR3中显示出非常有限的多样性，其中种系编码序列占所有序列的50%以上，并与典型的CDR3δ2相关联。此外，这些胎儿血液中的Vγ9Vδ2 T细胞在功能上是预先编程的（例如，干扰素-γ和颗粒酶-A/K），具有快速可激活的固有样T细胞的特性。因此，在出生后接触微生物之前，胎儿体内就已经发生了对磷酸抗原反应性效应T细胞的富集。在小鼠中，这些不同的特征与选择元件的作用有关，并且将在人与鼠γδ T细胞之间建立比通常所阐述的更强的平行关系。
