Systemic immune activity occurs during human immune system maturation.

The second trimester of pregnancy is a pivotal stage in human immune system development. Utilizing single-cell RNA sequencing and T cell receptor sequencing, we profiled 2,868,420 immune cells from 321 samples across 23 organs, including adult tissues as comparators. We identify an extrathymic CD4+ T cell subset mediating TOX2+ precursor cells' transition to mature naive CD4+ T cells. Contrary to the prevailing paradigm of fetal immune quiescence, we uncover widespread memory/activated T cells and tissue-resident memory clones shared across organs, indicating systemic immune activity beyond localized barrier defense. Cell-cell communication and functional assays indicate two tolerance mechanisms that suppress fetal T cell activation: ARG1+ neutrophils and a PTGES3/PTGER4 signaling pathway. We also find that hematopoietic stem cells (HSCs) disperse across multiple organs and show that HSCs from non-canonical hematopoietic organs differentiate into diverse immune lineages. These findings provide insights into human immune system maturation and tolerance in fetuses and adults.