T cells use focal adhesions to pull themselves through confined environments

Caillier, Alexia; Oleksyn, David; Fowell, Deborah J.; Miller, Jim; Oakes, Patrick W.

doi:10.1083/jcb.202310067

Cited by 3 publications

(1 citation statement)

References 97 publications

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“…Our results indicate that adherent blebby T cells can exhibit a highly migratory phenotype by increasing their contractility and fine-tuning their cortical stiffness to intermediate values. This mode of migration is consistent with a recent study that shows that T cells push and pull on the extracellular matrix and require adhesion-based forces to migrate through in vitro systems 134 . Recent experimental observations additionally support this hybrid mode of migration.…”

Section: Discussionsupporting

confidence: 92%

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

Alonso-Matilla,

Provenzano,

Odde

2023

Preprint

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ABSTRACT— 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 only 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 suggests that bleb-producing cells can employ a hybrid bleb- and adhesion-based migration mechanism for optimum cell motility and identifies conditions for optimality. 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 design criteria for engineered immune therapies and provides a physical perspective of the potential migratory mechanisms underlying rapid single-cell migration, particularly in the context of bleb-based/amoeboid migration.Significance StatementT-cell based cancer therapies present a promising approach to treating cancer. Solid tumors create a highly immunosuppressive and fibrotic microenvironment that obstructs the infiltration of cytotoxic T cells, thus promoting tumor growth and metastasis. Despite recent progress, there is still a gap in our understanding of the migration mechanisms used by T cells to mechanically move through tissue. Here we determine that while cell shape deformation-based cell swimming is possibly used as a short-term exploratory mechanism, its predicted associatedin vivomigration capabilities are suboptimal. Instead, our findings propose an alternative adhesion-based hybrid migration mechanism for optimal cell motility. This work provides important insights to aid design of cell engineering strategies to enhance migratory capabilities of antitumor immune cells.

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Section: Discussionsupporting

confidence: 92%

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

Alonso-Matilla,

Provenzano,

Odde

2023

Preprint

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Dynamic traction force measurements of migrating immune cells in 3D biopolymer matrices

Böhringer,

Cóndor,

Bischof

et al. 2024

Nat. Phys.

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Measurement of cellular traction forces during confined migration

Hockenberry,

Ulmer,

Rapp

et al. 2024

Preprint

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To migrate efficiently through tissues, cells must transit through small constrictions within the extracellular matrix. However, in vivo environments are geometrically, mechanically, and chemically complex, and it has been difficult to understand how each of these parameters contribute to the propulsive strategy utilized by cells in these diverse settings. To address this, we employed a sacrificial micromolding approach to generate polymer substrates with tunable stiffness, controlled adhesivity, and user-defined microscale geometries. We combined this together with live-cell imaging and three-dimensional traction force microscopy (TFM) to quantify the forces that cells use to transit through constricting channels. Surprisingly, we observe that cells migrating through compliant constrictions take longer to transit and experience greater nuclear deformation than those migrating through more rigid constrictions. TFM reveals that this deformation is generated by inwardly directed contractile forces that decrease the size of the opening and pull the walls closed around the nucleus. These findings show that nuclear deformation during confined migration can be accomplished by internal cytoskeletal machinery rather than by reactive forces from the substrate, and our approach provides a mechanism to test between different models for how cells translocate their nucleus through narrow constrictions. The methods, analysis, and results presented here will be useful to understand how cells choose between propulsive strategies in different physical environments.

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T cells use focal adhesions to pull themselves through confined environments

Cited by 3 publications

References 97 publications

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

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

Dynamic traction force measurements of migrating immune cells in 3D biopolymer matrices

Measurement of cellular traction forces during confined migration

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