Mice that lack activity of αvβ6-and αvβ8-integrins reproduce the abnormalities of Tgfb1- and Tgfb3-null mice

The arginine-glycine-aspartate (RGD)-binding integrins alpha v beta 6 and alpha v beta 8 activate latent TGF beta 1 and TGF beta 3 in vivo, but it is uncertain whether other RGD-binding integrins such as integrins alpha v beta 5 and alpha v beta 3 activate these TGF beta isoforms. To define the combined role of alpha v beta 6- and alpha v beta 8-integrin in TGF beta activation, we analyzed mice lacking function of both integrins by means of gene deletion and/or pharmacologic inhibition. Most Itgb6(-/-); Itgb8(-/-) embryos die at mid-gestation; those that survive develop cleft palate - as observed in Tgfb3(-/-) mice. Itgb8(-/-) mice treated with an anti-alpha v beta 6-integrin antibody develop severe autoimmunity and lack Langerhans cells - similar to Tgfb1-null mice. These results support a model in which TGF beta 3-mediated palate fusion and TGF beta 1-mediated suppression of autoimmunity and generation of Langerhans cells require integrins alpha v beta 6 and alpha v beta 8 but not other RGD-binding integrins as TGF beta activators.