Effector Vγ9Vδ2 T cell response to congenital Toxoplasma gondii infection.

Ling Ma,Maria Papadopoulou,Arnaud Marchant,Valeria Meroni,Francesca Genco,David Vermijlen,Martin Taton

doi:10.1172/jci.insight.138066

Abstract

A major γδ T cell population in human adult blood are the Vγ9Vδ2 T cells that are activated and expanded in a TCR-dependent manner by microbe-derived and endogenously derived phosphorylated prenyl metabolites (phosphoantigens). Vγ9Vδ2 T cells are also abundant in human fetal peripheral blood, but compared with their adult counterparts they have a distinct developmental origin, are hyporesponsive toward in vitro phosphoantigen exposure, and do not possess a cytotoxic effector phenotype. In order to obtain insight into the role of Vγ9Vδ2 T cells in the human fetus, we investigated their response to in utero infection with the phosphoantigen-producing parasite Toxoplasma gondii (T. gondii). Vγ9Vδ2 T cells expanded strongly when faced with congenital T. gondii infection, which was associated with differentiation toward potent cytotoxic effector cells. The Vγ9Vδ2 T cell expansion in utero resulted in a fetal footprint with public germline-encoded clonotypes in the Vγ9Vδ2 TCR repertoire 2 months after birth. Overall, our data indicate that the human fetus, from early gestation onward, possesses public Vγ9Vδ2 T cells that acquire effector functions following parasite infections.

Highlights

Introduction γδ T cells areT lymphocytes that express a TCR containing γ and δ chains, instead of α and β chains as in the conventional CD4+ and CD8+ αβ T cells
While Vγ9Vδ2 T cells are abundant in fetal peripheral blood, they are hyporesponsive toward phosphoantigen stimulation in vitro, they are highly regulated by programmed cell death protein 1, and they do not show a cytotoxic effector phenotype [10,11,12,13,14,15]
A main finding of our study was the presence among congenital Toxo+ infants of a fetal footprint in their γδ TCR repertoire, most likely because of the high expansion of fetal Vγ9Vδ2 T cells in utero

Summary

Introduction

Introduction γδ T cells areT lymphocytes that express a TCR containing γ and δ chains, instead of α and β chains as in the conventional CD4+ and CD8+ αβ T cells. A major γδ T cell population in human adult blood are the Vγ9Vδ2 T cells that are defined by the expression of a TCR containing the γ chain variable region 9 (Vγ9, TRGV9) and the δ chain V region 2 (Vδ2, TRDV2) They express a potent cytotoxic effector phenotype and are activated and expanded in a TCR-dependent manner by microbe- and host-derived phosphorylated prenyl metabolites (phosphorylated Ags, or phosphoantigens), derived from the isoprenoid metabolic pathway [4,5,6]. While Vγ9Vδ2 T cells are abundant in fetal peripheral blood, they are hyporesponsive toward phosphoantigen stimulation in vitro, they are highly regulated by programmed cell death protein 1, and they do not show a cytotoxic effector phenotype [10,11,12,13,14,15] These features are likely related to (tolerance) requirements of the fetal immune system, which involves a distinct thymic development [16,17,18]

Methods

Results

Conclusion