Baoyu Liu

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 receptor, its development, fate, and immune responses are governed by how that receptor engages its cognate antigen. Similarly, antibodies—the secreted forms of BCRs—depend on antigen binding to trigger effector functions like antibody-dependent cellular cytotoxicity (ADCC). By characterizing binding kinetics and structural mechanisms, we map these biophysical properties to downstream immune outcomes and leverage these insights to engineer therapeutic receptors and antibodies.

A defining feature of TCR and BCR interactions is that they occur at the interface of two opposing cell membranes, confining receptor–ligand binding to a two-dimensional (2D) plane. This contrasts with traditional three-dimensional (3D) measurements using recombinant proteins in solution. Because 2D and 3D kinetics differ in molecular degrees of freedom, they are physically distinct and often poorly correlated. Crucially, 2D interactions are regulated by the cellular membrane environment and mechanical forces - factors absent in conventional 3D assays. In TCR antigen recognition, 2D parameters like on-rate and affinity predict T cell responses far more accurately than 3D metrics. Moreover, TCR catch bonds - which strengthen under mechanical force - play vital roles in thymic selection as well as antiviral and antitumor immunity. We are now extending these insights to explore analogous 2D mechanisms in BCR antigen recognition.

 

Our research integrates experimental and computational tools to dissect T and B cell biology. We utilize mouse, humanized mouse, and human systems alongside ultrasensitive biophysical methods, such as the biomembrane force probe, to quantify 2D binding kinetics. To translate these insights, we combine phage display for novel antibody discovery with molecular dynamics simulations and targeted mutagenesis to guide rational molecular engineering. Currently, we investigate self-antigen recognition by autoimmune T cells in type 1 diabetes and rheumatoid arthritis, where we have uncovered distinct kinetic features unique to self-reactivity. Building on this 2D framework, we are expanding into B cell biology to generate antibodies targeting self-antigen recognition and engineer novel antibodies that enhance the efficacy and persistence of chimeric antigen receptor (CAR) T cell therapies.