T cell morphodynamics reveal periodic shape oscillations in three-dimensional migration.

T cells use sophisticated shape dynamics (morphodynamics) to migrate towards and neutralize infected and cancerous cells. However, there is limited quantitative understanding of the migration process in three-dimensional extracellular matrices (ECMs) and across timescales. Here, we leveraged recent advances in lattice light-sheet microscopy to quantitatively explore the three-dimensional morphodynamics of migrating T cells at high spatio-temporal resolution. We first developed a new shape descriptor based on spherical harmonics, incorporating key polarization information of the uropod. We found that the shape space of T cells is low-dimensional. At the behavioural level, run-and-stop migration modes emerge at approximately 150 s, and we mapped the morphodynamic composition of each mode using multiscale wavelet analysis, finding 'stereotyped' motifs. Focusing on the run mode, we found morphodynamics oscillating periodically (every approx. 100 s) that can be broken down into a biphasic process: front-widening with retraction of the uropod, followed by a rearward surface motion and forward extension, where intercalation with the ECM in both of these steps likely facilitates forward motion. Further application of these methods may enable the comparison of T cell migration across different conditions (e.g. differentiation, activation, tissues and drug treatments) and improve the precision of immunotherapeutic development.

Physics-informed deep learning characterizes morphodynamics of Asian soybean rust disease.

Medicines and agricultural biocides are often discovered using large phenotypic screens across hundreds of compounds, where visible effects of whole organisms are compared to gauge efficacy and possible modes of action. However, such analysis is often limited to human-defined and static features. Here, we introduce a novel framework that can characterize shape changes (morphodynamics) for cell-drug interactions directly from images, and use it to interpret perturbed development of Phakopsora pachyrhizi, the Asian soybean rust crop pathogen. We describe population development over a 2D space of shapes (morphospace) using two models with condition-dependent parameters: a top-down Fokker-Planck model of diffusive development over Waddington-type landscapes, and a bottom-up model of tip growth. We discover a variety of landscapes, describing phenotype transitions during growth, and identify possible perturbations in the tip growth machinery that cause this variation. This demonstrates a widely-applicable integration of unsupervised learning and biophysical modeling.