Biophysical modeling identifies an optimal hybrid amoeboid-mesenchymal phenotype for maximal T cell migration speeds*

Many cell types, including transformed cells and immune cells, such as T cells, can produce protrusive, blister-like plasma membrane patches initially devoid of F-actin, called blebs. Despite recent progress in understanding the amoeboid-mesenchymal migration phenotype balance, it remains largely unknown how bleb-producing cells mechanically move through complex environments and what factors set their migration speed and directionality. Here, we have developed a hybrid stochastic-mean field biophysical model of bleb-based cell motility to study the potential for adhesion-free bleb-based migration. We find that simulated cells can inefficiently migrate in the absence of adhesion-based forces, i.e., cell swimming, by producing high-to-low cortical contractility oscillations, where a high cortical contractility phase characterized by multiple bleb nucleation events is followed by an intracellular pressure buildup recovery phase at low cortical tensions, resulting in net cell motion. Our model identifies conditions for optimality for cell swimming (~1.5 mm²/min) and suggests that bleb-producing cells can employ a hybrid bleb- and adhesion-based migration mechanism for optimum cell motility. We find that blebs nucleate in subcellular regions of high cortical tension, low membrane-cortex linker density and high intracellular osmotic pressure. Lower extracellular matrix stiffnesses favor bleb growth, hence bleb-based cell swimming, which stands in contrast to classical mesenchymal/motor-clutch migration, where cell motility generally increases with increasing matrix stiffness. The developed model is expected to help generate designed criteria for engineered immune therapies and provides a physical perspective of the potential migratory mechanisms underlying single-cell migration, particularly in the context of bleb-based/amoeboid migration.