Our lab investigates antigen recognition by T cell receptors (TCRs) and B cell receptors (BCRs) - the molecular foundation of adaptive immunity. Once a T or B cell expresses a functional TCR/BCR receptor, its development, fate, and immune responses are governed by how that receptor interacts with its cognate antigen. Similarly, antibodies - the secreted forms of BCRs - depend on antigen binding to trigger effector functions like antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). By characterizing BCR/TCR binding kinetics and the underlying structural mechanisms, we aim to discover fundamental principles of adaptive antigen recognition and use these insights to engineer T/B cell functional responses for therapeutic applications.
Research Statement
Our lab investigates antigen recognition by T cell receptors (TCRs) and B cell receptors (BCRs), the molecular basis of adaptive immunity. Once a T or B cell successfully rearranges and expresses a functional TCR or BCR, its subsequent development, ultimate fate, and antigen-specific responses are largely determined by how that receptor interacts with its cognate antigen. Antibodies—the secreted form of BCRs—similarly depend on antigen binding to mediate effector functions such as antibody-dependent cellular cytotoxicity (ADCC). Our research seeks to define these receptor–antigen interactions by characterizing their binding kinetics and correlating these biophysical properties with downstream immune responses. We further investigate the structural and molecular mechanisms underlying these interactions and leverage these insights to engineer novel receptors and antibodies for therapeutic applications.
A defining feature of TCR and BCR interactions is that they occur at the interface of two opposing cell membranes, where receptor–ligand binding is confined to a two-dimensional (2D) plane. This is fundamentally different from the traditional three-dimensional (3D) measurements of TCR/BCR/antibody binding kinetics that are typically obtained using recombinant proteins in solution. Indeed, 2D and 3D kinetics are physically distinct because they differ in the degrees of freedom governing molecular movement and are often poorly correlated. More importantly, 2D interactions are regulated by the cellular membrane environment and by mechanical forces, factors that are absent in conventional 3D measurements.The significance of these distinctions has been clearly demonstrated in TCR antigen recognition. For example, we and others have shown that 2D kinetic parameters, such as on-rate and affinity, predict T cell responses more accurately than their 3D counterparts. In addition, TCR catch bonds—interactions that strengthen under mechanical force—play critical roles in thymic selection as well as antiviral and antitumor immunity. Building on these findings, we are interested in exploring analogous mechanisms in BCR antigen recognition.
Our research employs a broad range of experimental and computational approaches, including mouse, humanized mouse, and human systems to study T and B cell function; ultrasensitive biophysical techniques such as the biomembrane force probe to quantify 2D binding kinetics; phage display to generate novel antibodies; and molecular dynamics simulations and mutagenesis studies to guide molecular engineering strategies.
Our current work focuses on self-antigen recognition by autoimmune T cells in type 1 diabetes and rheumatoid arthritis, where we have identified kinetic features unique to self-reactivity that are not observed in conventional foreign antigen recognition. We are also extending the 2D framework to additional areas of B cell biology, including the development of antibodies targeting distinctive features of self-antigen recognition and the engineering of antibodies to improve the efficacy and persistence of chimeric antigen receptor (CAR) T cell therapies.
