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

Abstract

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.

Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection

“…Vδ1 + γδ T cells have a more diverse TCR repertoire and have been associated with adaptive responses, especially against viruses such as CMV (54,55). In the present study, an increased proportion of circulating TNF/IFN-γ-producing Vδ2 + γδ T cells were found in IRAK4-deficient individuals; these most likely expanded as a result of the recurrent infections in these patients (8).…”

“…In humans, Vδ2 + γδ T cells have a semi-invariant TCR repertoire and rapidly expand and contribute to host defense against microbial infections (54,55). Vδ1 + γδ T cells have a more diverse TCR repertoire and have been associated with adaptive responses, especially against viruses such as CMV (54,55).…”

High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates

“…Large clinical studies testing associations between functional MIF polymorphisms and MIF expression levels with susceptibility to or severity of neonatal sepsis are now required to substantiate whether MIF represents a potential attractive target for immune-modulating adjunctive therapies for neonatal sepsis. Adding to the recent studies challenging the idea that the neonatal immune system is purely immature (71)(72)(73)(74)(75), the recognition of a unique role for MIF in regulating innate immunity supports the concept that neonatal immune responses are tightly regulated by a balance of pro-and antiinflammatory mediators.…”

Aminobisphosphonates Synergize with Human Cytomegalovirus To Activate the Antiviral Activity of Vγ9Vδ2 Cells

“…The Vg9Vd2 T cell response to APB-induced phosphoantigen accumulation is TCR-and CD277 (butyrophilin BTN3A1)-dependent (7)(8)(9). Intracellular phosphoantigens can bind to the cytoplasmic domain of BTN3A1, and this interaction is sensed by the Vg9Vd2 TCR in a manner that is still incompletely understood but may involve a conformational rearrangement of BTN3 and other protein complexes such as periplakin and F1-ATPase, conferring the cells an increased sensitivity to Vg9Vd2 killing activity (10)(11)(12)(13)(14).…”