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

Moretti, Federico A.; Moser, Markus; Lyck, Ruth; Abadier, Michael Madgy Labib; Ruppert, Raphael; Engelhardt, Britta; Fässler, Reinhard (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 - PNAS, 110(42), pp. 17005-17010. National Academy of Sciences NAS 10.1073/pnas.1316032110

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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 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

UniBE Contributor:

Lyck, Ruth; Abadier, Michael Madgy Labib and Engelhardt, Britta

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0027-8424

Publisher:

National Academy of Sciences NAS

Language:

English

Submitter:

Ursula Zingg-Zünd

Date Deposited:

12 Jun 2014 15:04

Last Modified:

19 Nov 2015 10:38

Publisher DOI:

10.1073/pnas.1316032110

PubMed ID:

24089451

Uncontrolled Keywords:

EAE, integrin affinity

BORIS DOI:

10.7892/boris.46450

URI:

https://boris.unibe.ch/id/eprint/46450

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