NK Cell Activation as an Immune Mechanism in Depression: Insights from Single-Cell Multi-Omics
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Major depressive disorder (MDD) is associated with systemic immune dysregulation, but the specific immune cell populations and activation states contributing to disorder susceptibility remain poorly understood. Identifying these dynamic immune mechanisms may help uncover new opportunities for immune-targeted interventions in depression. We combined single-cell transcriptomic data from peripheral blood mononuclear cells (PBMCs) under resting and stimulated conditions with population genetic analyses to identify immune-cell populations and activation states linked to MDD susceptibility. Psoriasis was included as a comparator phenotype where ground truth regarding immune involvement is established. We identified immune-cell programmes enriched for disease-associated genetic risk and used Mendelian randomisation to prioritise genes potentially contributing to disease susceptibility. We find that psoriasis heritability predominantly localised to activated lymphocyte populations following CD3/CD28 stimulation, consistent with its established adaptive immune pathology. In contrast, MDD heritability was enriched within natural killer (NK) cell populations among resting and lipopolysaccharide (LPS)-stimulated PBMCs. Genetic analyses further prioritised NK-cell-associated genes, including CCL5 , GZMA and SYNE2 , with evidence of genetically predicted effects on MDD risk. By connecting genetic evidence for immune involvement in depression with specific cellular and functional contexts, our findings implicate NK-cell transcriptional programmes in MDD susceptibility, highlighting NK-cell immune signalling as a potential target for immunomodulatory treatment strategies.
Source: medRxiv
Institutions: University of Bristol, MRC Integrative Epidemiology Unit, RIKEN Center for Brain Science, Bristol NHS Foundation Trust, The University of Texas MD Anderson Cancer Center, King's College London, University of Cambridge, Avon and Wiltshire Mental Health Partnership NHS Trust, NIHR Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust
Language: English
Subfield: Biological Psychiatry
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: G140217044, Data mining epidemiological relationships, Psychosis Immune Mechanism Stratified Medicine Study (PIMS), CHECKPOINT: Finding immune & metabolic pathways to SMI, G4059666690, G4075591208, The South Wales and South West England Mental Health Platform Hub, G4260143917, Inflammation and Immunity in Depression: from novel mechanisms towards therapeutics, G4302154454, G462051784, G5189661712, G5350041710, G5625190163, Immunopsychiatry: Investigating the role of inflammation in depression and other psychiatric disorders, G6342754709, G6487373758, Inflammation and Immunity in Depression: from novel mechanisms towards therapeutics, Physical and mental health multimorbidity across the lifespan (LIfespaN multimorbidity research Collaborative (LINC))., G75805579, Leveraging large-scale molecular datasets to dissect immune-mediated pathways to disease and guide therapeutic opportunities, G8476933502, Leveraging large-scale molecular datasets to dissect immune-mediated pathways to disease and guide therapeutic opportunities, G942680792
OpenAlex ID: W7223702197