Abstract Text: We have previously published that human fetal T cells were susceptible to in utero microbial priming (Cell). This places in question the nature of fetal Treg dominance, and the scale of T cell maturation permitted during gestational development.To answer this question, we performed CyToF analysis of human fetal circulation, thymic and peripheral tissue (gut, liver, lung, mesenteric lymph nodes) compartments, to examine the profile of fetal T cells in a holistic manner. Comparing the fetal circulation against our age continuum immunome EPIC database (Nature Biotech), we detected a rare yet diverse memory spectrum. This spectrum of fetal T cell functional states originated from thymic imprinting but experienced memory expansion in peripheral fetal tissues. Restriction in TCR𝛼𝜷 CDR3 diversity in memory fetal tissue T effector cells indicated antigenic selection. Overall, this body of evidence supports the notion that the gestational environment is conducive for T cell maturation. Tissue fetal T effector maturation was functionally regulated by an early thymic-peripheral tissue wave of PD1+Ki67+Treg with strong suppressive capacity. Notably, memory bias in Th1 effectors across fetal tissues was correspondingly balanced by a specific regulatory arm of Tbet+Treg, with tissue infiltrations exceeding adult levels. Despite strong regulatory oversight, partial demethylation of the FoxP3 promoter locus in fetal Tregs points to limited lineage stability, suggesting a mechanism for residual programming for T effectors. Overall, beyond thymic imprinting, fetal T effectors in utero experiences antigenic memory expansion, that is precisely controlled by an immune regulatory rheostat.
