Math Biology Seminar: Libin Abraham

B cells integrate signals from multiple activating and inhibitory receptors in a highly regulated spatiotemporal manner to regulate B cell receptor (BCR) signaling and B cell activation. Marginal Zone (MZ) B cells are unique subset of B cells that exist in a partially activated ‘primed’ state, allowing them to rapidly respond to small amounts of antigens. The molecular basis for this priming is not fully understood. We propose that the priming of MZ B cells reflects altered lateral mobility and nanoscale organization of the BCR and other cell surface proteins, as compared to resting circulating follicular (FO) B cells. We have used high-speed single particle tracking and multi-color super-resolution microscopy to quantify receptor mobility and spatial organization, on the plasma membrane of FO and MZ B cells. We found that IgM, but not IgD BCRs in MZ B cells possess, (i) higher lateral mobility, (ii) larger confinement radius, and (iii) higher slowàfast state transition rates, when compared to FO B cells. Using a novel graph-theory based hierarchical clustering algorithm (StormGraph), we found that both IgM and IgD BCRs exist in larger nanoclusters on the surface of MZ B cells, when compared to FO B cells. Although both BCR isotypes exist in discrete and heterogeneous nanoscale protein islands in both B cell types, signaling BCRs predominantly overlap with IgM containing nanoclusters, when compared to IgD. Our data propose that interaction of IgM BCRs and ‘signaling hub’ protein islands in MZ B cells may result in greater antigen-independent tonic BCR signaling, contributing to the partially-activated ‘primed’ state of MZ B cells.