Hobson, R. | bioRxiv Science

bioRxiv2023

Clonal CD8 T cells in the leptomeninges are locally controlled and influence microglia in human neurodegeneration

Recent murine studies have highlighted a crucial role for the meninges in surveilling the central nervous system (CNS) and influencing CNS inflammation. However, how meningeal immunity is altered in human neurodegeneration and its potential effects on neuroinflammation is understudied. In the present study, we performed single-cell analysis of the transcriptomes and T cell receptor repertoire of 72,576 immune cells from 36 postmortem human brain and leptomeninges tissues from donors with neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimers disease, and Parkinsons disease. We identified the meninges as an important site of antigen presentation and CD8 T cell activation and clonal expansion and found that T cell activation in the meninges is a requirement for infiltration into the CNS. We further found that natural killer cells have the potential to negatively regulate T cell activation locally in the meninges through direct killing and are one of many regulatory mechanisms that work to control excessive neuroinflammation.

neuroscience↗

bioRxiv2021

Rapid 3D-STORM imaging of diverse molecular targets in tissue

The precise organization of fine scale molecular architecture is critical for the nervous system and other biological functions and would benefit from nanoscopic imaging methods with improved accessibility, throughput, and native tissue compatibility. Here, we report RAIN-STORM, a rapid and scalable imaging approach that enables three-dimensional nanoscale target visualization for multiple subcellular and intracellular targets within tissue at depth. RAIN-STORM utilizes conventional tissue samples, readily available reagents in optimized formulas, requires no specialized sample handling, and is suitable for commercial instrumentation. To illustrate RAIN-STORMs ability for quantitative high-resolution nanoscopic tissue imaging, we utilized the well-organized but structurally complex retina. We show that RAIN-STORM is rapid and versatile, enabling 3D nanoscopic imaging of over 20 distinct targets to reveal known and novel nanoscale features of synapses, neurons, glia, and vascular. Further, imaging parameters are compatible with a wide range of tissue sources and molecular targets across a spectrum of biological structures. Finally, we show that this method can be applied to clinically derived samples and reveal the nanoscale distribution of molecular targets within human samples. RAIN-STORM thus enables rapid 3D imaging for a range of molecules, paving the way for high throughput studies of nanoscopic molecular features in intact tissue from diverse sources.

neuroscience↗