Data-driven simulations elucidate how lymphocyte motility behaviors influence cell-cell interactions within germinal centers

Within the germinal center light zone, B cells and T cells rely on cell motility to engage in B-T interactions that enable antibody affinity maturation. Prior studies have shown that disrupting baseline lymphocyte motility behaviors can impair the germinal center response. However, the quantitative relationship between lymphocyte motility and B-T interactions in the germinal center is not well understood. A key challenge is that many in vivo imaging approaches require sparse cell labeling to segment and track individual cells within the dense germinal center microenvironment. This sparse labeling approach obscures a substantial fraction of B-T interactions within the tissue and limits the ability to map measured cell motility behaviors to emergent cell-cell interactions. A second challenge is that cell motility is intrinsically heterogeneous, with cell populations exhibiting a range of behaviors that are difficult to systematically relate to multi-cell interactions. To address these limitations, we developed a computational framework that allows us to 1) quantify heterogenous motility behaviors from intravital imaging data and 2) systematically predict how these measured behaviors lead to emergent cell-cell interactions. Applying unsupervised clustering, we identified seven distinct lymphocyte motility behaviors (B1-B7) from intravital imaging data. Notably, T-cells tended to take on fast, exploratory movements (B1-B4) while B cells tended to move in slower, confined paths (B5-B7). We then developed and validated a three-dimensional agent-based model to quantify the effect of these individual motility behaviors on B-T interactions. Our model predicted that B cells exhibiting slow motility behaviors (B5-B7) and T cells exhibiting fast motility behaviors (B1-B4) maximized the emergent number of unique B cell interactions per T cell within fixed observation volumes. These predictions suggest that the baseline differential motility behaviors of B cells and T cells enhance their ability to surveil for B-T interactions during the germinal center response.