Single cell genomics tools have expanded our view of many biological systems, often beyond our wildest dreams. In fact, recent single cell studies have advanced our understanding of the developing human immune system, specifically the role the individual organs play during gestation. While this work has broken ground for immunologists who study immune-related congenital disorders, what’s been lacking is a complete picture of this developmental process across all organs.
In this publication summary, we feature work using single cell multiomics and spatial gene expression to create an atlas of the developing immune system across organs and gestation (1). Not only will this map have far-reaching use in the areas of cell engineering and regenerative medicine, it has potential to greatly further our knowledge of immune development and related conditions and disorders.
Expanding our view of the developing immune system across organs and gestation
Only a few years ago, the aim of the International Human Cell Atlas initiative would have been fantastical: to build a reference map of all cells in the human body to better understand health and disease.
As single cell technologies have evolved—and become a mainstay in studies that aim to create cell atlases based on transcriptomic data—Sarah Teichmann’s group, alongside many other partner groups at the Wellcome Sanger Institute in the UK, have published an increasing number of studies characterizing developing human organs (2–5) in both health and disease.
Although these studies have provided profound insight into singular prenatal organs, a recent publication led by Chenqu Suo, a PhD student in the Teichmann group, offers a first look into the prenatal immune system as a network across organs and gestational time. The dataset profiles nine tissues and, compared to previous cell atlases that include more than one organ (6), their developmental atlas includes a greater number of organs and stages of gestation, increases sequencing depth, and integrates single cell RNA sequencing (scRNA-seq), antigen receptor sequencing, and spatial transcriptomic data to build a map of how the immune system develops across time and space.
Combining Chromium Single Cell Gene Expression with Single Cell Immune Profiling (SCIP) and Visium Spatial Gene Expression (Visium), the researchers performed scRNA-seq on cells from yolk sac, prenatal spleen, and skin (spanning human tissue samples from 4 to 17 weeks after conception), and then integrated publicly available cell atlases of six additional organs. In all, they looked across prenatal hematopoietic (yolk sac, liver, and bone marrow), lymphoid (thymus, spleen, and lymph node), and nonlymphoid peripheral organs (skin, kidney, and gut), including over 900,000 cells encompassing more than 100 cell states. They added paired γδ T-cell receptor (TCR), αβ TCR, and B-cell receptor (BCR) sequencing data, followed by spatial transcriptomic data on prenatal spleen, liver, and thymus (early hematopoietic tissue and lymphoid organs critical for B- and T-cell development).
A mixed bag: Prenatal myeloid and lymphoid cells are heterogeneous across organs and gestation
In essence, they found a substantial amount of heterogeneity across both prenatal myeloid (from the bone marrow) and lymphoid (from the lymph nodes and/or thymus) cells when they looked across organs and gestational age. For example, one piece of their cross-tissue analysis allowed them to identify three subtypes of monocytes distributed between prenatal bone marrow and peripheral tissues. Another interesting finding from their cross-organ analysis revealed that monocytes and T cells share conserved processes of proliferation and maturation before they migrate out of the bone marrow and thymus, respectively, into peripheral tissues.
Across gestation, they discovered “compositional shifts,” for example, myeloid progenitor cells decreasing in the liver but increasing in the bone marrow. Notably, their cross-gestation analysis revealed an interesting discovery: myeloid cell types including macrophages, mast cells, and NK cells acquire immune effector functions (based on these cells’ transcriptomes) during the first trimester (between 10 and 12 weeks post-conception), and they may contribute to angiogenesis, tissue morphogenesis, and homeostasis.
Blood and immune cells develop across all peripheral organs
Research dogma says that hematopoiesis only happens in the yolk sac, liver, and bone marrow during human development during the first and second trimester. However, the team was surprised to find hematopoietic progenitors in non-hematopoietic organs. Specifically, for example, they found B-cell progenitors in almost all prenatal organs and myeloid progenitors in the thymus, spleen, skin, and kidney. Using Visium and single-molecule fluorescence in situ hybridization, they localized B-cell progenitors specifically to the developing gut, thymus, and spleen as well as liver.
More findings make surprising discoveries of innate B and T cells
Taking together single cell transcriptomic and BCR information (from their SCIP analysis), as well as functional validation data, they were able to identify human prenatal innate-like B and T cells, as well as extensively characterize human B1 cells.
By integrating transcriptomic profiles of human prenatal unconventional T cells (cells that are not of the conventional CD4+, CD8+, or Treg types), immune profiling data from TCR sequencing (of γδ TCRs and αβ TCRs), and scRNA-seq data from an in vitro thymic organoid culture model, they found evidence of thymocyte–thymocyte selection during development of these unconventional T cells. In other words, these kinds of T cells may originate from positive selection on neighboring T cells (7).
Toward an improved understanding of immunological health and disease
This first-of-its-kind single cell and spatial atlas provides a comprehensive understanding of the developing human immune system, adding not only more data to build out the Human Cell Atlas but also providing a resource for the fields of in vitro cell engineering and regenerative medicine, the authors say. It could also impact our understanding of the mechanisms behind congenital disorders affecting the immune system as well as help define the precise immunological roles that innate-like B and T cells play in the prenatal immune system.
- Suo C, et al. Mapping the developing human immune system across organs. Science 376: eabo0510 (2022). doi: 10.1126/science.abo0510
- Popescu D-M, et al. Decoding human fetal liver haematopoiesis. Nature 574: 365–371 (2019). doi: 10.1038/s41586-019-1652-y
- Stewart BJ, et al. Spatiotemporal immune zonation of the human kidney. Science 365: 1461–1466 (2019). doi: 10.1126/science.aat5031
- Park J-E, et al. A cell atlas of human thymic development defines T cell repertoire formation. Science 367: eaay3224 (2020). doi: 10.1126/science.aay3224
- Elmentaite R, et al. Single-cell sequencing of developing human gut reveals transcriptional links to childhood Crohn’s disease. Dev Cell 55: 771–783.e5 (2020). doi: 10.1016/j.devcel.2020.11.010
- Cao J, et al. A human cell atlas of fetal gene expression. Science 370: eaba7721 (2020). doi: 10.1126/science.aba7721
- Georgiev H, et al. Classical MHC expression by DP thymocytes impairs the selection of non-classical MHC restricted innate-like T cells. Nat Commun 12: 2308 (2021). doi: 10.1038/s41467-021-22589-z