Altered NK Cell Receptor Profiles and Immune-Inflammatory Markers in Adolescent Major Depressive Disorder: Associations with Cognitive Impairment

Abstract Background Immune dysregulation and cognitive deficits are increasingly recognized in adolescent major depressive disorder (MDD), yet their interrelationship remains unclear. This study aimed to investigate peripheral immune-inflammatory alterations and natural killer (NK) cell phenotypes, and explore their association with cognitive function in adolescent MDD. Methods Fifty-four first-episode, drug-naïve adolescents with MDD and 33 matched healthy controls (HCs) were enrolled. Group differences in peripheral blood immune-inflammatory indices (NLR, PLR, MLR, SII, SIRI), NK cell surface receptors (HLA-DR, NKp46, NKp30, NKG2A, NKG2C, KIR2DL1, ILT2, CD57), and cognitive function were analyzed, along with their intercorrelations. Results Compared with HCs, patients with MDD showed lower NEU, NLR, PLR, and SII levels, alongside elevated LYM counts. NK cells exhibited reduced overall proportions but increased expression of HLA-DR, NKp46, NKG2A, and ILT2, with decreased CD57 expression in the MDD group. Significant cognitive impairments were observed in speed of processing, reasoning and problem solving, and social cognition. Furthermore, several immune-inflammatory markers (MLR, SII, SIRI) and NK cell receptors (HLA-DR, NKG2C, NKp30, CD57) were significantly correlated with performance across multiple cognitive domains. Conclusion Our findings reveal significant associations between NK cell phenotypes, systemic immune-inflammatory markers, and cognitive function in adolescent MDD. These results suggest a potential regulatory role of NK cells within the immune–cognitive axis, possibly reflecting both intermediary functions and inflammation-independent neuroimmune mechanisms. This study provides novel insight into potential biomarkers and immunomodulatory targets for early intervention in adolescent MDD.