Mapping the developing human immune system across organs

Abstract

Recent advances in single cell genomics technologies have facilitated studies on the developing immune system at unprecedented scale and resolution. However, these studies have focused on one or a few organs and were thus limited in understanding the developing immune system as a distributed network across tissues. Here, we profiled prenatal haematopoietic organs, lymphoid organs and non-lymphoid tissues using a combination of single-cell RNA sequencing, paired antigen-receptor sequencing and spatial transcriptomics to reconstruct the developing human immune system. Our analysis revealed the acquisition of immune effector transcriptome profiles in macrophages, mast cells and NK cells from the second trimester, and the transcriptomic changes accompanying the late-stage maturation of developing monocytes and T cells that extended from their organ of origin to peripheral tissues. We uncovered system-wide blood and immune cell development beyond the conventional primary haematopoietic organs. We further identified, extensively characterised and functionally validated the human prenatal B1 cells. Finally, we provide evidence for thymocyte-thymocyte selection origin for αβTCR- expressing unconventional T cells based on TCR gene usage and an in vitro artificial thymic organoid culture model. Our comprehensive atlas of the developing human immune system provides both valuable data resources and biological insights that will facilitate cell engineering, regenerative medicine and disease understanding.

scDREAMER: atlas-level integration of single-cell datasets using deep generative model paired with adversarial classifier

“…While we restricted our analysis for the integration of scRNA-seq datasets, our deep generative model encompasses a general framework which can accommodate other omics datasets and we plan to extend the framework of scDREAMER to multiomics datasets. Finally, given the rapid generation of atlas-level single-cell datasets (32; 33; 34) across multiple organs and species, we anticipate scDREAMER to become an invaluable method for performing scalable and accurate integration of single-cell atlases for the exploration of different biological systems.…”

A Multi-scale, Multiomic Atlas of Human Normal and Follicular Lymphoma Lymph Nodes

“…A chief aim of several international consortia is the construction of organ atlases from healthy and diseased human populations (Liu and Zhang, 2022; Regev et al, 2017; Rozenblatt-Rosen et al, 2020; Snyder et al, 2019). These efforts are focused on generating atlases from human organs and tissues using next generation sequencing (NGS) and spatial approaches such as multiplexed antibody-based imaging (Börner et al, 2021; Conde et al, 2022; Eraslan et al, 2022; Hickey et al, 2021; Jones et al, 2022; Suo et al, 2022). The lymph node (LN) offers unique challenges and opportunities due to its importance in host immune responses, structural and cellular diversity, distribution in >500 discrete units throughout the human body, and involvement in metastasis and hematological malignancies (Grant et al, 2020; Swerdlow et al, 2016).…”

Single-cell reference mapping to construct and extend cell-type hierarchies

“…Reference mapping methods have changed the traditional paradigm of manual and time-consuming cell annotation and novel cell type discovery. Recent efforts to build organ- and body-scale cell atlases in collaborative efforts within consortia such as the human cell atlas (HCA) have leveraged reference mapping to make their resources public for individual users and labs, annotate new datasets, and identify novel cell types by disease to healthy references [5–11]. As a result, users can contextualize their datasets within these references to identify novel cell types from healthy to disease-specific variations and thus enabling the discovery of disease-affected cell types that can be prioritized for treatment design.…”