The ability of T cells to migrate through diverse tissues is critical for immune surveillance, yet their infiltration into fibrotic tumors is often limited. T cell migration has been primarily studied in microporous collagen matrices or microfabricated channels that allow cells to simply squeeze through the pre-existing paths. However, such methods do not fully capture the complexities of moving through nanoporous extracellular matrices (ECMs) found in soft tissues, where T cells are often required to create their own migration paths. Further, soft tissues and ECM mechanics are complex, exhibiting varied viscoelasticity (time dependent mechanical response), plasticity (irreversible deformation in response to forces), and shear strength (stress at which material ruptures). Here, we studied T cell migration in three-dimensionally confining collagen-rich hydrogels with a range of stiffness, viscoelasticity, plasticity, and shear strength. Strikingly, only shear strength, not stiffness or viscoelasticity, correlated with migration. During migration, T cells extend actin-rich, finger-like protrusions into the matrices, which then undergo a divergent breaststroke-like motion, locally rupturing the matrix to create a passage. We determined that this migration is critically dependent on actin polymerization, while myosin contractility plays a supporting role. Moreover, we found that β1-integrin interactions with collagen-1 were essential for migrating through matrices with high shear strengths. Furthermore, T cells were immobile in hydrogels exhibiting the high shear strength of pancreatic adenocarcinomas but mobile in those exhibiting the shear strength of normal pancreatic tissues. Together, these findings reveal that T cells tear apart confining ECMs using a breaststroke-like motion to migrate, identify matrix shear strength as the key regulator of the migration, and suggest that enhanced shear strength in fibrotic tumors may hinder T cell infiltration.
Ha et al. (Sun,) studied this question.