Using Infiltrating Adaptive Immune Cell Signatures from Single‐Nucleus Profiling to Identify Neuroimmune Interactions in Parkinson’s Disease

Abstract

AbstractBackgroundAffected brain areas in Parkinson’s disease (PD) show infiltration of T cells, together with increased expression of pro‐inflammatory cytokines and microglia with activated morphology, suggesting that neuroinflammation is plays a complex role in this disorder. To begin elucidating the mechanisms by which infiltrating adaptive immune cells may contribute to the demise of neurons in PD, we sought to investigate changes in T cell transcriptional signatures at the single‐cell level in post‐mortem human tissue. We also investigated the transcriptional signatures of microglia to capture interactions between the innate and adaptive immune system.MethodWe applied a single nucleus RNA‐sequencing approach to generate an unbiased transcriptomic dataset in 19 sporadic PD cases across the substantia nigra (SN), ventral tegmental area, substantia innominata, and hypothalamus, and in the SN of 14 controls.ResultWe identified three subpopulations of CD8+ T cells which are enriched in the PD SN, and a natural killer (NK) cell population is enriched in the SN of controls. These findings parallel those of other studies that show CD8+ T cells are enriched in the PD brain, and those that suggest NK cells may play a protective role against disease. In parallel, we identified a microglial subpopulation that is present in the SN of controls but depleted in SN tissue from donors with PD; this microglial population has higher expression of antigen‐presentation proteins, suggesting unique interactions with the adaptive immune system. Immune cell‐cell interactions between the identified T cell, NK cell, and microglial subpopulations were investigated through assessing co‐regulation of ligand‐receptor pairs. Unique interactions were found in the PD SN which are suggestive of recruitment of activated microglial populations to the SN by T cells, as well as T cell and microglial inhibition of NK cell signaling.ConclusionThese findings suggest an imbalance between CD8+ T cell and NK cell activity in the PD SN, and a role for T cells in microglial activation in PD. We aim to integrate our immune genomic data with neuronal data to generate a signature of neuroimmune interactions in PD, which may ultimately be used to develop biomarkers and candidate molecules/pathways to therapeutically target specific immune interactions.