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Regulation of antibody responses by B cell mechanical activity

Periodic Reporting for period 3 - BCELLMECHANICS (Regulation of antibody responses by B cell mechanical activity)

Reporting period: 2018-09-01 to 2020-06-30

The production of antibodies against pathogens is an effective mechanism of protection against a wide range of infections. However, some pathogens evade antibody responses by rapidly changing their composition. Designing vaccines that elicit antibody responses against invariant parts of the pathogen is a rational strategy to combat existing and emerging pathogens. Production of antibodies is initiated by binding of B cell receptors (BCRs) to foreign antigens presented on the surfaces of antigen presenting cells. This binding induces B cell signalling and internalisation of the antigens for presentation to helper T cells. Although it is known that T cell help controls B cell expansion and differentiation into antibody-secreting and memory B cells, how the strength of antigen binding to the BCR regulates antigen internalisation remains poorly understood. As a result, the response and the affinity maturation of individual B cell clones are difficult to predict, posing a problem for the design of next-generation vaccines. Our aim is to develop understanding of the cellular mechanisms that underlie critical B cell activation steps. Our laboratory has recently described that B cells use mechanical forces to extract antigens from antigen presenting cells. We hypothesise that application of mechanical forces tests BCR binding strength and thereby regulates B cell clonal selection during antibody affinity maturation and responses to pathogen evasion. We propose to test this hypothesis by (1) determining the magnitude and timing of the forces generated by B cells, and (2) determining the role of the mechanical properties of BCR-antigen bonds in affinity maturation and (3) in the development of broadly neutralising antibodies. We expect that the results of these studies will contribute to our understanding of the mechanisms that regulate the antibody repertoire in response to infections and have practical implications for the development of vaccines.
Our research goals in the first reporting period were to determine the forces that B cells use to extract antigens from immune synapses in vitro.
To this end, we developed new DNA-based nanosensors to measure cellular pulling forces. Using these sensors we showed that naïve B cells use low forces to extract antigens, whereas germinal centre B cells use high forces. This difference in mechanics of germinal centre B cells accompanies dramatically different architecture of their immune synapses and makes them more sensitive to antigen affinity. We conclude that germinal centre B cell mechanics likely contributes to selection of high affinity B cell clones during affinity maturation.
To understand mechanisms of B cell antigen extraction under physiological conditions, we modified the DNA sensors to report on antigen extraction from live antigen presenting cells. These experiments showed that B cells indeed use mechanical forces to acquire antigens from dendritic cells or follicular dendritic cells, two cell types involved in antigen presentation to B cells during antibody responses. However, B cells can resort to enzymatic liberation of the antigen if force-mediated extraction fails. This may be important for B cell antigen processing in situations when force mediated extraction is impossible, such as in autoreactive B cells recognising cartilage. In addition, force mediated-antigen extraction from antigen presenting cells is regulated by the physical stiffness of the presenting cells. Dendritic cells are soft and allow extraction of even low affinity antigen via low forces. In contrast, follicular dendritic cells are stiff and promote stringent affinity discrimination. Thus, distinct mechanical properties of antigen presenting cells promote different types of responses, with dendritic cells supporting sensitive activation of naïve cells, whereas follicular dendritic cells support affinity selection in germinal centres.
Our studies so far argue for an important role of B cell and antigen presenting cell mechanics that may be important for antibody responses. This new information opens a potential to modulate responses to vaccines in the future, for example by changing the physical properties of antigens and their presentation.
Schematic of B cell mechanical extraction of antigens