Integrin αvβ8-Mediated TGFβ Activation by Effector Regulatory T-cells is Essential for Suppression of T-cell-Mediated Intestinal Inflammation

Foxp3+ regulatory T-cells (Tregs) play a pivotal role in suppressing self-harmful T-cell responses to prevent inflammatory bowel disease. An important cytokine in the development and function of Tregs is TGFβ, a latent cytokine that must be activated to function. Evidence suggests that T-cells need to respond to TGFβ in order for Treg-mediated suppression to occur in the intestine. Yet, how TGFβ is regulated to promote this suppression is poorly understood. We now show that both mouse and human Tregs have high expression of the TGFβ-activating integrin αvβ8, which enables these cells to activate high levels of latent TGFβ. However, deletion of integrin αvβ8 expression from Tregs resulted in no overt inflammatory phenotype at rest, indicating that the integrin plays little role in controlling immunity during homeostasis. Strikingly, we find that integrin αvβ8 expression and function is highly upregulated on an activated/effector Treg subset marked by KLRG1, and that Tregs lacking expression of integrin αvβ8 were unable to function as suppressive cells during models of colitis in vivo. Thus, we have uncovered an essential mechanism by which effector Tregs suppress T-cells during intestinal inflammation, highlighting a key role for Treg-mediated activation of latent-TGF-beta in suppression of self-harmful T-cell responses. Our work therefore highlights a novel pathway that could be therapeutically targeted to treat inflammatory bowel disease.