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Human Kidney Immune Cell Map Reveals Multiple Infection Protection Zones

NEW YORK – Researchers at the Wellcome Sanger Institute, the University of Cambridge, Newcastle University, and elsewhere have generated a cell atlas of the human kidney and used it to map the organ's communities of immune cells.

In a study published today in Science, the researchers said they used single-cell RNA sequencing to resolve the spatiotemporal immune topology of the human kidney, finding anatomically defined expression patterns of immune genes within the epithelial compartment, and antimicrobial peptide transcripts in pelvic epithelium in the mature kidney.

"A network of tissue-resident myeloid and lymphoid immune cells was evident in both fetal and mature kidney, with postnatal acquisition of transcriptional programs that promote infection-defense capabilities," the authors wrote. "Epithelial-immune cross-talk orchestrated localization of antibacterial macrophages and neutrophils to the regions of the kidney most susceptible to infection."

The principal infectious challenge in the kidney comes from bacteria ascending the ureter into the kidney pelvis, the researchers noted, adding that the hypersaline environment of the medulla may promote antimicrobial responses.

For their study, they performed droplet encapsulation high-throughput single-cell RNA sequencing (scRNAseq) on the 10x Genomics platform, as well as flow and mass cytometry to define the global immune landscape of the human kidney. They studied single-cell suspensions from 14 mature human kidneys and six fetal kidneys, capturing 114,113 droplets from mature kidneys, which yielded 40,268 cells.

They then used a principal component analysis to identify clusters of cells and manually separated them into four major cellular compartments on the basis of canonical marker expression: endothelial, immune, fibroblast and myofibroblast, and epithelium.

Within the endothelial cell clusters, the researchers identified glomerular endothelial (GE) cells, vasa recta (VR) cells, and peritubular capillaries (PCaps). Immune cell populations included mononuclear phagocytes (MNPs), B cells, T cells, and natural killer cells. To explore the spatial distribution of these cells across the kidney, the researchers assigned a depth estimate of the sample from which the cells originated, which they termed pseudodepth. They observed an enrichment of GE, podocytes, and PT cells in samples predicted to be cortical or corticomedullary in pseudodepth, and found that pelvic epithelium (PE) and transitional epithelium cells were limited to medulla or pelvic pseudodepth.

"This analysis revealed an asymmetrical distribution of immune cells; B cells were almost exclusively located in cortical samples, whereas MNPs were enriched in deeper samples," the authors noted.

They also analyzed single-cell transcriptomes from fetal kidneys, capturing 33,865 droplets, which yielded 27,203 annotated cells. There, the team identified immune, endothelial, developing nephron epithelium, and stromal cell clusters by canonical marker expression.

The fetal kidney dataset revealed several immune cell clusters: Macrophages and some dendritic cells (DCs) were present at the earliest developmental stage. Monocytes, T cells, and NK cells appeared starting at nine weeks after conception, whereas B cells were present starting at 12 weeks post conception.

"These data demonstrate that immune cell subsets exhibit different temporal patterns of localization to the human fetal kidney," the researchers wrote. "Terminally differentiated fetal nephron epithelial cells showed transcriptional similarity to their mature counterparts, particularly in proximal nephron components, whereas [connecting nephron tubules (CNT)] and PE showed less similarity."

They also verified a pattern of immune gene expression across the mature nephron, particularly in the PE, including innate-immune and antimicrobial-response genes. Bulk transcriptomic data similarly demonstrated the highest expression of immune genes in the pelvis. By contrast, there was little or no expression of immune genes in fetal kidney epithelium.

Further, the team found that distinct expression patterns of antimicrobial peptides (AMPs) in the human kidney likely facilitate protective epithelial responses in the region most vulnerable to ascending bacterial infection, and suggested that these multiple zones of epithelial innate immune capability are acquired postnatally.

"Here, we investigated immune capability in the human kidney and determined how it changes over developmental time and anatomical space. We found that antimicrobial immunity is spatially zonated but this feature was not evident prenatally," the authors concluded. "Fetal kidney epithelium showed little immune gene expression, consistent with the view that it occupies a relatively sterile environment, where anatomically polarized antimicrobial defense is redundant. We show that a variety of immune cell populations are established in the human kidney in the first trimester with distinct temporal patterns, but they differ from mature kidney immune cells, with postnatal acquisition of transcriptional programs that promote proinflammatory and infection defense capabilities."