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  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., et al. (2013). Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 110(42), 17005-17010. doi:10.1073/pnas.1316032110.

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 Creators:
Moretti, Federico A.1, Author              
Moser, Markus2, Author
Lyck, Ruth2, Author
Abadier, Michael2, Author
Ruppert, Raphael1, Author              
Engelhardt, Britta2, Author
Fässler, Reinhard1, Author              
Affiliations:
1Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565147              
2external, ou_persistent22              

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Free keywords: EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; MULTIPLE-SCLEROSIS; LEUKOCYTE ADHESION; CATCH BONDS; AFFINITY; RECEPTOR; ROLES; AUTOIMMUNITY; ENDOTHELIUMintegrin affinity; EAE;
 Abstract: Activated T cells use very late antigen-4/alpha 4 beta 1 integrin for capture, rolling on, and firm adhesion to endothelial cells, and use leukocyte function-associated antigen-1/alpha L beta 2 integrin for subsequent crawling and extravasation. Inhibition of alpha 4 beta 1 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 naive 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 alpha 4 beta 1 and alpha L beta 2 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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Language(s): eng - English
 Dates: 2013
 Publication Status: Published in print
 Pages: 6
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000325634200067
DOI: 10.1073/pnas.1316032110
 Degree: -

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Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Source Genre: Journal
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Publ. Info: 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA : NATL ACAD SCIENCES
Pages: - Volume / Issue: 110 (42) Sequence Number: - Start / End Page: 17005 - 17010 Identifier: ISSN: 0027-8424