Abstract: Disclosed are methods for enriching and expanding antigen-specific T cells with paramagnetic nanoparticles comprising a major histocompatibility complex (MHC) or human leukocyte antigen (HLA) and a costimulatory molecule bound thereto. The platform eliminates the requirement of cell isolation and can be further adapted to be high throughput with the capability of processing multiple antigen-specific T cells in parallel. Accordingly, the disclosed methods provide a high-throughput workflow for the identification and analysis of antigen-specific T cell responses.