Abstract
Abstract
T cell migration is primarily viewed as a cytoskeletal process. Here, we show that chemokine-stimulated CD8
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T cell migration is modulated by a volume-driven biophysical switch at the plasma membrane (PM). We found that chemokine-induced cell swelling creates an adhesion-dependent gradient of high PM fluidity at the leading edge. External chemical fluidisation of the PM using membrane modulators enhances migration similar to chemokine-induced fluidisation without the need of cell-swelling. Together, our findings identify PM fluidity as a tuneable biophysical gatekeeper that controls T cell migration, potentially providing a novel mechanical tool for optimising adoptive cell therapies in restrictive tissue microenvironments.
One sentence summary
Chemokine-induced cell swelling increases plasma membrane fluidity at the leading edge to support actin retrograde flow dynamics.
Significance Statement
Immune cells must move rapidly through the body to find and eliminate threats, but how they physically control movement has remained unclear. We show that chemokine signals trigger T cells to take up water and swell, causing their plasma membrane to become more fluid. This local membrane fluidization reduces mechanical resistance at the cell front, enabling the actin cytoskeleton to push the membrane forward and drive migration. Importantly, cell adhesion concentrates this fluid state at the leading edge, creating a spatial cue that directs movement. Our findings identify the plasma membrane as an active mechanical regulator of cell migration and provide a new framework for understanding immune-cell behavior, cancer-cell invasion, and the design of more effective cell-based immunotherapies.