Engineering the T cell receptor for fun and profit: Uncovering complex biology, interrogating the immune system, and targeting disease.

T cell receptors (TCRs) orchestrate cellular immunity by recognizing peptide antigens bound and presented by major histocompatibility complex (MHC) proteins. Due to the TCR's central role in immunity and tight connection with human health, there has been significant interest in modulating TCR properties through protein engineering methods. Complicating these efforts is the complexity and vast diversity of TCR-peptide/MHC interfaces, the interdependency between TCR affinity, specificity, and cross-reactivity, and the sophisticated relationships between TCR binding properties and T cell function, many aspects of which are not well understood. Here we review TCR engineering, starting with a brief historical overview followed by discussions of more recent developments, including new efforts and opportunities to engineer TCR affinity, modulate specificity, and develop novel TCR-based constructs.