Regulatory T (Treg) cells play a pivotal role in suppressing self-harmful T cell responses, but how Treg cells mediate suppression to maintain immune homeostasis and limit responses during inflammation is unclear. Here we show that effector Treg cells express high amounts of the integrin αvβ8, which enables them to activate latent transforming growth factor-β (TGF-β). Treg-cell-specific deletion of integrin αvβ8 did not result in a spontaneous inflammatory phenotype, suggesting that this pathway is not important in Treg-cell-mediated maintenance of immune homeostasis. However, Treg cells lacking expression of integrin αvβ8 were unable to suppress pathogenic T cell responses during active inflammation. Thus, our results identify a mechanism by which Treg cells suppress exuberant immune responses, highlighting a key role for effector Treg-cell-mediated activation of latent TGF-β in suppression of self-harmful T cell responses during active inflammation. Display omitted •Human and mouse effector Treg cells express functional TGF-β-activating integrin αvβ8•Treg cell integrin αvβ8-mediated TGF-β activation is not needed for T cell homeostasis•Integrin αvβ8 expression by Treg cells suppresses active inflammation•Pathway could be targeted to promote Treg-cell-mediated suppression of inflammation Regulatory T (Treg) cells suppress harmful T cell responses, but mechanisms mediating suppressive function during homeostasis versus inflammation are poorly defined. Travis and colleagues show that activation of the cytokine TGF-β by effector Treg cells, via expression of integrin αvβ8, is crucial for Treg-cell-mediated suppression of inflammatory T cells.