Quantitative investigation of mechanosensing in B cell activation

B cell activation is triggered by specific binding events between the B cell receptor (BCR) and antigen molecules presented by antigen-presenting cells (APCs). B cell activation is well-characterised biochemically but the influence of physical factors, such as force and geometry, is less well understood. Preliminary data from the Spillane laboratory shows that B cell activation increases monotonically with substrate rigidity and that decreasing antigen density leads to a reduction in the rigidity threshold for activation. This suggests that B cell activation can be regulated not only by force but also antigen spacing. During my PhD project, I will continue to investigate the relationship between antigen density, geometry and substrate rigidity, with the aim of developing a quantitative understanding of BCR mechanosensing. This will feed into the second part of my PhD, where I will use DNA origami to investigate more precisely how B cell activation is influenced by the nanoscale arrangement of antigen and hence how valency and cooperativity of BCR-antigen binding influences B cell activation. I will investigate the mechanosensitivity of different BCR isotypes to elucidate how the spatial tolerance of the BCR changes with structure, which is important for understanding how different B cell populations respond to antigen. Together, this work is important for the rational design of new vaccines and immunotherapies.