Decoding the human prenatal immune system with single-cell multi-omics

The human immune system is made up of a huge variety of cell types each with unique functions. Local networks of resident immune cells are poised to sense and protect against pathogen entry, whereas more widespread innate and adaptive immune networks provide first rapid, then long-lasting and targeted responses. However, how we develop such a diverse and complex system remains unknown. Studying human development directly has been challenging in the past, but recent advances in single-cell and spatial genomics, together with the co-ordinated efforts of the Human Cell Atlas and other initiatives, have led to new studies that map the development of the human immune system in unprecedented detail. In this Review, we consider the timings, transitions, cell types and tissue microenvironments that are crucial for building the human immune system. We also compare and contrast the human system with model species and in vitro systems, and discuss how an understanding of prenatal immune system development will improve our knowledge of human disease. Single-cell multi-omic profiling has revealed how the immune system is established in the human embryo, mapping in unprecedented detail the emergence of progenitors, the handover of haematopoiesis between sites and the diversification of cell lineages across the body.