Tissue-resident immunity in the human kidney

The human kidney maintains whole organism homeostasis through tightly regulated filtration, transport, and endocrine functions that are subserved by a wide array of specialised cell types with distinct developmental origins and anatomical organisation. Amongst these cells lies a network of tissue-resident immune cells with incompletely characterised roles in tissue homeostasis, repair, and defence. Furthermore, different regions of the kidney are affected by distinct immunologically relevant insults - ascending bacterial infection in the medullary-pelvic region, and immune complex-mediated inflammation within the cortex. We hypothesised that the kidney-resident immune network is adapted to respond to and counter these immunological challenges. Recently the advent of high-throughput single-cell genomics methods has permitted the atlasing of human organs in unprecedented molecular detail. These techniques permit the unbiased characterisation of cell types and cell states, the prediction of functional programmes, and the mapping of intercellular interaction networks underpinning tissue organisation. In this thesis, we used single-cell RNA sequencing to generate the first detailed and spatio-temporally resolved atlas of the human kidney in development and maturity. This study has identified the transcriptional signatures of mature kidney parenchymal cell types from nephron epithelial, vascular, and stromal compartments, and allowed the reconstruction of the developmental trajectories of early nephrogenesis. Within the immune compartment, we charted the landscape of immune cells, and the seeding of these cells through early development, identifying a macrophage subset in mature kidneys with transcriptional similarity to macrophages seeded early in fetal life, and likely representing a long-lived self-renewing subset. This work also identified a transcriptional signature mediating antimicrobial defence in the pelvis of the kidney. Here pelvic epithelial cells express antimicrobial peptides, and neutrophil- and monocyte-recruiting chemokines, orienting the immune response towards the dominant infectious threat. We later optimised and refined the single-cell genomics approach to the human kidney, generating high quality data on a larger panel of donors in a compartmentally-resolved fashion. In this work we were able to assess the immune composition of glomerular and tubulointerstitial compartments, finding a strikingly divergent immune landscape, with glomeruli occupied by monocytes, dendritic cells, and NK cells, and the tubulointerstitial compartment housing populations of resident macrophages, T cells, and B cells. Finally we have begun to explore the dynamic transcriptional responses of kidney immune and parenchymal cells to IgG immune-complex stimulation using an ex vivo normothermic normoxic perfusion model. These experiments have uncovered cell type-specific signalling responses in stimulated monocytes, NK cells, and glomerular endothelial cells, with evidence for abundant chemokine and cytokine signalling coordinating the early response to this highly disease-relevant perturbation.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2022

Author dc:creator

• Stewart, Benjamin

Advisors dc:contributor.advisor

• Clatworthy, Menna
• Teichmann, Sarah

• immunity
• kidney
• nephrology
• macrophage
• developmental biology
• single cell genomics
• inflammation

Licence

• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.92268

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/344845