NKG2A and NKp30 expression in NK cells correlates with preserved white matter and cortical thickness and reduced negative symptoms in psychiatric disorders

Background and hypothesis Immune dysregulation contributes to the pathophysiology of schizophrenia (SZ) and bipolar disorder (BD), but specific immune alterations remain unclear. Natural killer (NK) cells, regulated by a balance of activating and inhibitory receptors, are increasingly implicated in neuroimmune interactions. We hypothesized that distinct NK cell receptor expression patterns may identify patient subgroups characterized by preserved brain structure and reduced symptom burden. Study design We conducted deep immunophenotyping and unsupervised clustering of NK cells from 53 patients (32 BD, 21 SZ) and 25 healthy controls (HC). Frequencies of NK subsets defined by main receptor expression were examined. A subset of 58 participants also underwent MRI to assess cortical thickness and white matter microstructure. Associations between immune profiles, imaging measures and clinical symptoms were tested. Study results Across clustering models, we consistently identified a patient-specific cluster (PSI) characterized by increased NKG2A+NKp30+ NK cells and reduced double-negative (NKG2A−NKp30−) NK cells. This pattern was independent of classical CD56-based maturation. Patients in the PSI cluster showed preserved cortical thickness and white matter integrity compared with patients outside the cluster, who exhibited widespread reductions relative to HC controls. Furthermore, reduced double-negative NK frequencies correlated with lower burden of negative symptoms. Conclusions Co-expression of NKp30 and NKG2A defines a meaningful NK cell phenotype associated with immune regulation, preserved brain structure, and improved clinical outcomes in SZ and BD. This profile may represent a marker of immune resilience and neuroimmune homeostasis, with potential implications for early diagnosis, patient stratification, and novel therapeutic strategies.