Moretti, FA; Moser, M; Lyck, R; Abadier, M; Ruppert, R; Engelhardt, B; Fassler, R; (2013) Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells. Proceedings of the National Academy of Sciences , 110 (42) pp. 17005-17010. 10.1073/pnas.1316032110.

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Abstract

Activated T cells use very late antigen-4/α4β1 integrin for capture, rolling on, and firm adhesion to endothelial cells, and use leukocyte function-associated antigen-1/αLβ2 integrin for subsequent crawling and extravasation. Inhibition of α4β1 is sufficient to prevent extravasation of activated T cells and is successfully used to combat autoimmune diseases, such as multiple sclerosis. Here we show that effector T cells lacking the integrin activator Kindlin-3 extravasate and induce experimental autoimmune encephalomyelitis in mice immunized with autoantigen. In sharp contrast, adoptively transferred autoreactive T cells from Kindlin-3–deficient mice fail to extravasate into the naïve CNS. Mechanistically, autoreactive Kindlin-3–null T cells extravasate when the CNS is inflamed and the brain microvasculature expresses high levels of integrin ligands. Flow chamber assays under physiological shear conditions confirmed that Kindlin-3–null effector T cells adhere to high concentrations of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, albeit less efficiently than WT T cells. Although these arrested T cells polarize and start crawling, only few remain firmly adherent over time. Our data demonstrate that the requirement of Kindlin-3 for effector T cells to induce α4β1 and αLβ2 integrin ligand binding and stabilization of integrin–ligand bonds is critical when integrin ligand levels are low, but of less importance when integrin ligand levels are high.

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