Prenatal development of human immunity

Abstract

The blood and immune systems develop in parallel during early prenatal life. Waves of hematopoiesis separated in anatomical space and time give rise to circulating and tissue-resident immune cells. Previous observations have relied on animal models, which differ from humans in both their developmental timeline and exposure to microorganisms. Decoding the composition of the human immune system is now tractable using single-cell multi-omics approaches. Large-scale single-cell genomics, imaging technologies, and the Human Cell Atlas initiative have together enabled a systems-level mapping of the developing human immune system and its emergent properties. Although the precise roles of specific immune cells during development require further investigation, the system as a whole displays malleable and responsive properties according to developmental need and environmental challenge.

Fig. 1. Temporal and spatial development of the human immune system.

The development of blood and immune systems during early human life occurs over several anatomical sites. The major site of hematopoiesis changes from the extraembryonic yolk sac to the intraembryonic AGM, liver, and BM. T cell differentiation and maturation are confined to the thymus. Immune cells seed other lymphoid or peripheral organs—including lymph nodes, skin, intestine, kidney, and lung—and adapt to the respective organ environment. Diverse immune cell types develop and mature at different gestational stages, which is necessary to establish tolerance and functional response based on developmental needs. This prepares the developing embryo and fetus for antigen exposure during pregnancy and after birth. ILCP, ILC precursor; CDR3, complementary-determining region 3; TdT, terminal deoxynucleotidyl transferase.

Fig. 2. Overview of single-cell studies detailing the developing human immune system.

Diverse single-cell methods (depicted in color) have been applied to generate a comprehensive atlas of human immune system development. In many studies, multiple organs have been sampled together to investigate the migration, adaptation, and compartmentalization of immune cells. (Studies are indicated by the reference number, and dotted lines link the different organs sampled in each study.)

Fig. 3. Key questions to be addressed in future studies of immune system development.

The diagram depicts pertinent questions relating to the developing immune system. How do the HSCs change in their potential throughout development? How do diverse hematopoietic niches differ from each other? What determines the migration of immune cells to the target organs, and how do they adapt to a new tissue environment? Single-cell profiling and spatial profiling techniques are now providing answers to these questions by assessing the immune system as a whole and identifying emergent properties of the collective.