Other - Developmental Immunology
During development in utero, many human fetal immune cells are predisposed towards tolerogenic responses. Compared to adult human counterparts, human fetal naïve CD4 T cells exhibit a higher propensity for differentiation into tolerogenic regulatory T cells (TReg), and human fetal hematopoietic stem and progenitor cells (HSPCs) generate CD4 T cell progeny that are predisposed to TReg differentiation. After birth, naïve T cells must transition toward a more mature state that supports protection against pathogens and cancer. At the time of birth, it is unknown whether adult-associated protective programs are fully expressed, either universally within most naïve T cells, or heterogeneously within just a subset. Here, through single-cell transcriptional profiling of both naïve T cells and HSPCs, from fetal, full-term newborn umbilical cord blood, and adult human sources, we demonstrate that the fetal to adult transition is incomplete across most cord blood naïve T cells and their hematopoietic stem cell progenitors. Cells expressing a fully adult-like transcriptional signature are rare in cord blood, where most naïve T cells and HSPCs exhibit a distinct, intermediate transcriptional state. Our results provide a mechanism that might explain why many vaccines, which were largely designed around elicitation of immunity in the protection-predisposed adult immune system, show reduced efficacy in neonates. Continued analyses of how expression of specific gene programs vary across ages will be carried out with the translational aim of informing specific ways that targeted, tolerogenic or protective, therapeutic responses might be elicited in both cord blood transplant and neonatal vaccination interventions.