NK Cell Activation as an Immune Mechanism in Depression: Insights from Single-Cell Multi-Omics

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.