B Cell Antigen Extraction is Regulated by Physical Properties of Antigen Presenting Cells

Abstract

B cells play a critical role in immune responses by producing antibodies against the foreign pathogens that they encounter. Their responses are initiated when the B cell receptor (BCR) binds antigen on the surface of an antigen-presenting cell (APC) in a cell-cell contact known as the immune synapse. This event triggers the B cell to internalize, process, and present the antigen to helper T cells, which provide signals that are required for full B cell activation and clonal selection. High affinity B cells receive more T cell help than low affinity B cells do, suggesting that affinity discrimination during antigen extraction and internalization is essential for high-affinity antibody responses. The mechanisms of antigen recognition, discrimination, and uptake remain a topic of debate, with physical extraction through mechanical forces and enzymatic liberation through lysosome secretion proposed as efficient ways for B cells to acquire antigen. To investigate B cell extraction mechanisms, we developed DNA-based nanosensors to interrogate antigen extraction from both artificial substrates and live APCs. We show that B cells acquire antigen primarily through mechanical force, and resort to enzymatic liberation only if force-dependent extraction fails. The use of mechanical force renders B cells sensitive to the physical properties of the APCs. We find that stiff APCs promote strong B cell pulling forces and stringent affinity discrimination, while flexible APCs allow B cells to extract low-affinity antigen using weak forces. Thus, B cell antigen extraction is regulated by the physical properties of immune synapses, suggesting that distinct physical properties of APCs may support different stages of B cell responses.