Altered NK cell receptor profiles and immune-inflammatory markers in adolescent major depressive disorder: associations with cognitive impairment

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. CONCLUSION: Exploratory analyses suggested potential links between immune measures and cognitive performance, which require confirmation in larger samples. The observed immune and cognitive alterations warrant further investigation into potential neuroimmune mechanisms in adolescent MDD. This study provides novel insight into potential biomarkers and immunomodulatory targets for early intervention in adolescent MDD. CLINICAL TRIAL NUMBER: Not applicable.