CD20+ natural killer cells are polyfunctional, memory-like cells that are enriched in inflammatory disorders.

While CD20 was initially characterized as a B cell-specific marker, its expression on memory T cells has expanded our understanding of this molecule's distribution and function. Here, we identify a previously unrecognized CD20-expressing NK cell population and demonstrate its functional significance. CD56+CD20+ NK cells exhibit hallmarks of cellular activation, including elevated NKp46, CD69, and CD137 expression, enhanced proliferative capacity, and increased production of inflammatory cytokines (IFN-γ, GM-CSF, TNF-α, IL-10). Functional analyses revealed enhanced cytotoxicity against K562 targets, correlating with increased expression of cytolytic mediators including granzymes A, B, and K, perforin, FASL, and TRAIL. Single-cell transcriptional profiling demonstrated that MS4A1-expressing NK cells possess a distinct molecular signature characterized by elevated granzyme K expression and memory-like features. These cells preferentially localize to secondary lymphoid organs and accumulate in inflammatory tissues. Notably, CD56+CD20+ NK cells are enriched in multiple inflammatory conditions, including multiple sclerosis, autoimmune hepatitis, hepatitis B infection, hepatocellular carcinoma, and lung cancer. Treatment with rituximab depletes this population, suggesting potential therapeutic implications. Our findings establish CD20+ NK cells as a functionally distinct lymphocyte subset with enhanced effector capabilities and tissue-homing properties, providing new insights into immune regulation in inflammatory diseases.