Th187 - Hypo-functionality of Fetal Tregs Allow for a Permissive Regulatory Environment for Gestational T Effector Memory Maturation in Humans

Abstract Text: The gestational environment is frequently perceived to be predominantly suppressive and incompatible for T effector function maturation. However, evidence of a competent effector fetal environment in humans has been mounting. Herein in this study, we employed a high parametric, mass-cytometry based approach to investigate the fetal circulatory and micro-environmental immunomes, with an aim to understand the inception and extent of fetal effector T cell priming and its relation with regulatory mechanisms. We uncovered evidence of fetal thymic immune imprinting, coupled with both systemic and tissue effector memory development in human fetuses. Correspondingly, in the regulatory compartment, we detected the unique presence of thymic Tbet+Treg in fetal tissues at elevated levels as compared to adult tissues. Intriguingly, fetal Tregs in lung tissues, though capable of suppression, were hypo-suppressive as compared with adult counterparts. We discovered that a proportion of fetal Tregs lost FoxP3 commitment during expansion and exhibited higher TCR clonatype sharing with effector T cells, altogether reflecting higher plasticity in fetal Tregs than adult. Furthermore, epigenetic profiling of the FoxP3 promoter locus reveals that fetal Tregs were only partially de-methylated resulting in lineage instability. In summary, our data provide evidence of a gestational regulatory environment that is permissive for T effector functional maturation due to relative instability and hypo-functionality of fetal Tregs.