Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells

Moretti F.A.; Moser M.; Lyck R.Abadier M.Ruppert R.Engelhardt B.F?ssler R.

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Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells

机译：Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells

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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 na?ve 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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《Proceedings of the National Academy of Sciences of the United States of America》 |2013年第42期|17005-17010|共6页
作者
Moretti F.A.; Moser M.; Lyck R.Abadier M.Ruppert R.Engelhardt B.F?ssler R.;
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作者单位

Department of Molecular Medicine, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany;

Theodor Kocher Institute, University of Bern, CH-3012 Bern, Switzerland;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Eae; Integrin affinity;

Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells

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