Immune defense requires the capacity to respond to ever-changing pathogens and cancers while remaining tolerant to self. The Koh lab focuses on understanding the design principles in immune development that allow flexibility in cellular fate and function, and how these mechanisms are subverted in human disease. A major emphasis is to identify determinants that allow thymic epithelia to ectopically express thousands of tissue-specific self-antigens (e.g. insulin) to promote tolerance against harmful self-reactive T cells and prevent autoimmunity (e.g. diabetes). Another focus is to understand how T cells acquire competence to deploy diverse arrays of effector functions, and how this plasticity relates to leukemogenesis. We employ a broad, interdisciplinary approach combining genetics, genomics, biochemistry and proteomics, with particular investment in developing multi-omics methods to interrogate chromatin accessibility, gene expression, and cell-surface proteins from the same single cell. Elucidating how cellular plasticity is programmed in development, and dysregulated in disease, will avail novel therapeutic avenues for human disorders.