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Integrin cross-talk modulates stiffness-independent motility of CD4+ T lymphocytes.

ABSTRACT: To carry out their physiological responsibilities, CD4+ T lymphocytes interact with various tissues of different mechanical properties. Recent studies suggest that T cells migrate upstream on surfaces expressing intracellular adhesion molecule-1 (ICAM-1) through interaction with leukocyte function-associated antigen-1 (α_Lβ₂) (LFA-1) integrins. LFA-1 likely behaves as a mechanosensor, and thus we hypothesized that substrate mechanics might affect the ability of LFA-1 to support upstream migration of T cells under flow. Here we measured motility of CD4+ T lymphocytes on polyacrylamide gels with predetermined stiffnesses containing ICAM-1, vascular cell adhesion molecule-1 (VCAM-1), or a 1:1 mixture of VCAM-1/ICAM-1. Under static conditions, we found that CD4+ T cells exhibit an increase in motility on ICAM-1, but not on VCAM-1 or VCAM-1/ICAM-1 mixed, surfaces as a function of matrix stiffness. The mechanosensitivity of T-cell motility on ICAM-1 is overcome when VLA-4 (very late antigen-4 [α₄β₁]) is ligated with soluble VCAM-1. Last, we observed that CD4+ T cells migrate upstream under flow on ICAM-1-functionalized hydrogels, independent of substrate stiffness. In summary, we show that CD4+ T cells under no flow respond to matrix stiffness through LFA-1, and that the cross-talk of VLA-4 and LFA-1 can compensate for deformable substrates. Interestingly, CD4+ T lymphocytes migrated upstream on ICAM-1 regardless of the substrate stiffness, suggesting that flow can compensate for substrate stiffness.

SUBMITTER: Kim SHJ

PROVIDER: S-EPMC8684734 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In order to perform critical immune functions at sites of inflammation, circulatory T lymphocytes must be able to arrest, adhere, migrate and transmigrate on the endothelial surface. This progression of steps is coordinated by cellular adhesion molecules (CAMs), chemokines, and selectins presented on the endothelium. Two important interactions are between Lymphocyte Function-associated Antigen-1 (LFA-1) and Intracellular Adhesion Molecule-1 (ICAM-1) and also between Very Late Antigen-4 (VLA-4) and Vascular Cell Adhesion Molecule-1 (VCAM-1). Recent studies have shown that T lymphocytes and other cell types can migrate upstream (against the direction) of flow through the binding of LFA-1 to ICAM-1. Since upstream migration of T cells depends on a specific adhesive pathway, we hypothesized that mechanotransduction is critical to migration, and that signals might allow T-cells to remember their direction of migration after the flow is terminated. Cells on ICAM-1 surfaces migrate against the shear flow, but the upstream migration reverts to random migration after the flow is stopped. Cells on VCAM-1 migrate with the direction of flow. However, on surfaces that combine ICAM-1 and VCAM-1, cells crawl upstream at a shear rate of 800 s-1 and continue migrating in the upstream direction for at least 30 minutes after the flow is terminated-we call this 'migrational memory'. Post-flow upstream migration on VCAM-1/ICAM-1 surfaces is reversed upon the inhibition of PI3K, but conserved with cdc42 and Arp2/3 inhibitors. Using an antibody against VLA-4, we can block migrational memory on VCAM-1/ICAM-1 surfaces. Using a soluble ligand for VLA-4 (sVCAM-1), we can promote migrational memory on ICAM-1 surfaces. These results indicate that, while upstream migration under flow requires LFA-1 binding to immobilized ICAM-1, signaling from VLA-4 and PI3K activity is required for the migrational memory of CD4+ T cells. These results indicate that crosstalk between integrins potentiates the signal of upstream migration.

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Integrin cross-talk modulates stiffness-independent motility of CD4+ T lymphocytes.

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