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Using single-cell technologies to map the human immune system — implications for nephrology

Nature Reviews Nephrology volume 16, pages 112–128 (2020)Cite this article

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Abstract

Advances in single-cell technologies are transforming our understanding of cellular identity. For instance, the application of single-cell RNA sequencing and mass cytometry technologies to the study of immune cell populations in blood, secondary lymphoid organs and the renal tract is helping researchers to map the complex immune landscape within the kidney, define cell ontogeny and understand the relationship of kidney-resident immune cells with their circulating counterparts. These studies also provide insights into the interactions of immune cell populations with neighbouring epithelial and endothelial cells in health, and across a range of kidney diseases and cancer. These data have translational potential and will aid the identification of drug targets and enable better prediction of off-target effects. The application of single-cell technologies to clinical renal biopsy samples, or even cells within urine, will improve diagnostic accuracy and assist with personalized prognostication for patients with various kidney diseases. A comparison of immune cell types in peripheral blood and secondary lymphoid organs in healthy individuals and in patients with systemic autoimmune diseases that affect the kidney will also help to unravel the mechanisms that underpin the breakdown in self-tolerance and propagation of autoimmune responses. Together, these immune cell atlases have the potential to transform nephrology.

Key points

  • Single-cell technologies have enabled the mapping of immune cell populations in the kidney, the circulation, and secondary lymphoid tissues in unprecedented detail.

  • A variety of single-cell technologies have become mainstream over the last 5 years, including high-throughput single-cell RNA sequencing (scRNA-seq), single-cell chromatin accessibility assays and mass cytometry.

  • scRNA-seq has enabled researchers to interrogate the transcriptional diversity present in specific cell populations, for example, in circulating dendritic cells and monocytes, and create large-scale atlases profiling the landscape of tissues.

  • Using trajectory analysis, single-cell methods can reveal snapshots of dynamic processes such as cellular differentiation and responses to different immune stimuli.

  • Analysis of scRNA-seq data enables an assessment of how antigen-specific B and T lymphocyte clones expand in vivo in different tissue and disease states.

  • scRNA-seq data also enable ligand–receptor interactions to be explored in an unbiased manner, allowing novel cell signalling networks to be identified.

  • Single-cell studies have also uncovered disease-associated cell states and gene expression profiles, deepening our understanding of disease mechanisms and potentially identifying therapeutic targets.

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Fig. 1: Localization of immune cells in the circulatory system, secondary lymphoid organs and non-lymphoid organs.
Fig. 2: scRNA-seq technologies.
Fig. 3: Mapping immune cells in peripheral blood.
Fig. 4: Mapping immune cells in lymphoid organs.
Fig. 5: Mapping immune cells in the kidney.

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Acknowledgements

B.J.S. is supported by a Wellcome Trust Clinical Training Fellowship (216366/Z/19/Z), and a Cancer Research UK predoctoral bursary (A25230). J.R.F. is supported by the NIHR Cambridge Blood and Transplant Research Unit in Organ Donation. M.R.C. is supported by the National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre, by a Chan-Zuckerberg Initiative Human Cell Atlas Technology Development Grant, a Medical Research Council New Investigator Research Grant (MR/N024907/1), an Arthritis Research UK Cure Challenge Research Grant (21777), and an NIHR Research Professorship (RP-2017–08-ST2–002).

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  1. Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK

    Benjamin J. Stewart, John R. Ferdinand & Menna R. Clatworthy

  2. Cellular Genetics, Wellcome Sanger Institute, Cambridge, UK

    Benjamin J. Stewart, John R. Ferdinand & Menna R. Clatworthy

  3. Cambridge NIHR Biomedical Research Centre, Cambridge, UK

    Benjamin J. Stewart, John R. Ferdinand & Menna R. Clatworthy

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Glossary

scATAC-seq

Cell assay for transposase accessible chromatin with high-throughput sequencing is a sequencing-based assay that detects open regions of chromatin.

Mass cytometry

Use of a modified mass spectrometer to measure the binding of heavy metal tagged antibodies attached to target cells to infer protein expression levels at single-cell resolution.

High-dimensional data

Data characterized by a high number of simultaneous measurements (dimensions) measured for each sample. In the case of single-cell RNA sequencing, a large number of genes is measured for each cell.

Droplet microfluidics

Formation of individual droplets through combination or reagents within an oil suspension to form individual barcoded reaction vessels.

Cellular barcoding

Labelling the cDNA or RNA originating from a single cell with a DNA barcode, which, once sequenced, enables the tracing back of each individual sequenced transcript to the cell of origin.

Cell atlas

A large-scale census of cell types and states found in a tissue or a collection of tissues. Typically, such datasets contain tens or hundreds of thousands of cells and are powered to detect minority populations (<1% of the total).

Cell clustering

An approach to the partition of sets of cells into communities with similar gene or protein expression profiles.

Subcapsular sinus macrophages

A layer of macrophages positioned in the subcapsular sinus of the lymph node, where they are poised to sample antigens in lymph.

Splenic red pulp macrophages

Macrophages within the red pulp regions of the spleen with specialized roles in the phagocytosis of senescent and damaged erythrocytes, and iron recycling.

Marginal zone macrophages

Macrophages positioned within the marginal zone of the spleen, where they are poised to sample antigens in the blood.

Innate lymphoid cells

(ILCs). Lymphocytes that lack somatically rearranged antigen-specific receptors.

Peristalsis

Rhythmic contraction and relaxation of the smooth muscle lining a viscus, resulting in wave-like propulsion of its contents.

Massively parallel scRNA-seq

A method of single-cell RNA sequencing (scRNA-seq) in which cells are first sorted into individual wells, before undergoing lysis and reverse transcription.

T cell receptor reconstruction

A method for identifying the specific rearranged sequences of T cell receptors in single-cell RNA sequencing data.

Drop-seq

Early microfluidics-based droplet sequencing method where the microfluidics were assembled by the end user.

inDrop

A droplet microfluidics single-cell RNA sequencing approach in which cells are encapsulated into droplets and combined with oligonucleotide labelled hydrogel microspheres.

Fc receptor pathway

Intracellular signalling cascade downstream of ligation of Fc receptors by the Fc portion of immunoglobulin.

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Stewart, B.J., Ferdinand, J.R. & Clatworthy, M.R. Using single-cell technologies to map the human immune system — implications for nephrology. Nat Rev Nephrol 16, 112–128 (2020). https://doi.org/10.1038/s41581-019-0227-3

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