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Single-cell mapping of progressive fetal-to-adult transition in human naïve T cells

Abstract

Whereas the human fetal immune system is poised to generate immune tolerance and suppress inflammation in utero, an adult-like immune system emerges to orchestrate anti-pathogen immune responses in post-natal life. Compared to their adult counterparts, fetal naïve T cells more readily differentiate into tolerance-prone regulatory T cells (Tregs) upon stimulation, and fetal monocytes exhibit distinct responses to cytokine stimulation and impaired antigen presentation capacity. It is believed that tolerogenic responses across various immune cells are adaptations that allow the fetal immune system to suppress responses to non-inherited maternal antigens that might otherwise lead to pregnancy complications. After birth, the balance between tolerance versus protection must shift. It has been posited that cells of the adult immune system arise as a discrete ontological “layer” of hematopoietic stem-progenitor cells (HSPCs) and their progeny; evidence supporting this model in humans has, however, been inconclusive. Although it has been shown that various immune cell transitions during early gestation may be modeled by the layering hypothesis, it is unknown whether the transition from fetal-to-adult follows a similar mechanism. Here, we combine bulk and single-cell transcriptional profiling of lymphoid, myeloid, and HSPCs from fetal, perinatal, and adult developmental stages to demonstrate that the fetal-to-adult transition occurs progressively along a continuum of maturity—with a substantial degree of interindividual variation at the time of birth—rather than via a transition between discrete waves. We find that (1) newborn immune cells are relatively homogenous, each with an intermediate transitional phenotype, rather than having either a fetal or adult phenotype, (2) UCB HSPCs are not fully adult-transitioned, (3) the progression of transition at birth shows a high degree of inter-individual variability, and (4) pathways known to affect T cell polarization are among those expressed more highly in newborn than adult naïve CD4 T cells. These findings have important implications in the design of strategies for prophylaxis against infection in the newborn, and for the use of umbilical cord blood (UCB) in the setting of transplantation. I also present dittoSeq, a universal bulk and single-cell visualization toolkit that powered the analysis of these data. dittoSeq visualizations are color blindness-friendly by default, robustly documented to power ease-of-use by both novice and experienced coders, and allow highly customizable generation of both daily-use and publication-quality figures.

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