Release of Active TGF-β1 from the Latent TGF-β1/GARP Complex on T Regulatory Cells Is Mediated by Integrin β8

Activated T regulatory cells (Tregs) express latent TGF-beta 1 on their cell surface bound to GARP. Although integrins have been implicated in mediating the release of active TGF-beta 1 from the complex of latent TGF-b1 and latent TGF-beta 1 binding protein, their role in processing latent TGF-beta 1 from the latent TGF-beta 1/GARP complex is unclear. Mouse CD4(+)Foxp3(+) Treg, but not CD4(+) Foxp3(-) T cells, expressed integrin beta(8) (Itgb8) as detected by quantitative RT-PCR. Itgb8 expression was a marker of thymically derived (t)Treg, because it could not be detected on Foxp3(+)Helios(-) Tregs or on Foxp3(+) T cells induced in vitro. Tregs from Itgb8 conditional knockouts exhibited normal suppressor function in vitro and in vivo in a model of colitis but failed to provide TGF-beta 1 to drive Th17 or induced Treg differentiation in vitro. In addition, Itgb8 knockout Tregs expressed higher levels of latent TGF-beta 1 on their cell surface consistent with defective processing. Thus, integrin alpha(v)beta(8) is a marker of tTregs and functions in a cell intrinsic manner in mediating the processing of latent TGF-beta 1 from the latent TGF-beta 1/GARP complex on the surface of tTregs.