B cell receptors and free antibodies have different antigen-binding kinetics

Abstract

Receptor binding and triggering are central in Immunology as T cells activated through their T cell receptors (TCR) by protein antigens orchestrate immune responses. In order to understand receptor ligandinteractions, many groups working with different experimental techniques and assays have generated a vast body of knowledge during the last decades. However, in recent years a type of assays, referred to as two-dimensional or membrane-to-membrane [1], has questioned our current understanding of the role of different kinetic constants (for instance, on- versus off-rate constants) on TCR-ligand interaction and subsequent T cell activation. Here we present a general mathematical framework that provides a unifying umbrella to relate fundamental and effective (or experimentally determined) kinetic constants, as well as describe and compare state-of-the-art experimental methods [2].On the other hand, in vivo, B cell receptor (BCR)–antigen interactions occur in a 2-dimensional (2D) environment with antigen anchored to a membrane. Conversely, antibody–antigen interactions typically occur in a 3-dimensional (3D) environment [3]. The rotation necessary for the reactive sites (paratope in BCR and antibody and epitope in antigen) to align is a crucial factor in the binding reaction’s kinetic rates, but its impact has been underestimated and currently is unknown. Combining theory and existing empirical data, our study provides the first estimation of approximate 2D and 3D global rotational rates of BCR and antibody paratopes and estimates of 2D and 3D effective kinetic rates based on intrinsic binding rates. Our work also allows to estimate unavailable 2D rates from existing 3D data [4].