| First Author | Moretti FA | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 42 | Pages | 17005-10 |
| PubMed ID | 24089451 | Mgi Jnum | J:201988 |
| Mgi Id | MGI:5516395 | Doi | 10.1073/pnas.1316032110 |
| Citation | Moretti FA, et al. (2013) Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells. Proc Natl Acad Sci U S A 110(42):17005-10 |
| abstractText | Activated T cells use very late antigen-4/alpha4beta1 integrin for capture, rolling on, and firm adhesion to endothelial cells, and use leukocyte function-associated antigen-1/alphaLbeta2 integrin for subsequent crawling and extravasation. Inhibition of alpha4beta1 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 alpha4beta1 and alphaLbeta2 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. |
