Absence of integrin-mediated TGFβ1 activation in vivo recapitulates the phenotype of TGFβ1-null mice

The multifunctional cytokine transforming growth factor (TGF) beta 1 is secreted in a latent complex with its processed propeptide (latency-associated peptide [LAP]). TGF beta 1 must be functionally released from this complex before it can engage TGF beta receptors. One mechanism of latent TGF beta 1 activation involves interaction of the integrins alpha v beta 6 and alpha v beta 8 with an RGD sequence in LAP; other putative latent TGF beta 1 activators include thrombospondin1, oxidants, and various proteases. To assess the contribution of RGD-binding integrins to TGF beta 1 activation in vivo, we created a mutation in Tgfb1 encoding a nonfunctional variant of the RGD sequence (RGE). Mice with this mutation (Tgfb1(RGE/RGE)) display the major features of Tgfb1(-/-) mice (vasculogenesis defects, multiorgan inflammation, and lack of Langerhans cells) despite production of normal levels of latent TGF beta 1. These. ndings indicate that RGD-binding integrins are requisite latent TGF beta 1 activators during development and in the immune system.