An inhibitory receptor–ligand pair does more than stifle immune responses—it helps the cells that stifle immune responses, report Francisco and colleagues.

Regulatory T (T reg) cells halt aggressive immune responses before they cause damage. But too many T reg cells can obstruct a needed response against cancer or infection. Now, Francisco et al. reveal that the inhibitory programmed death (PD) 1 pathway, known to induce tolerance, promotes T reg cell activity by stimulating and maintaining the expression of Foxp3, the signature T reg cell transcription factor.

In mice lacking PD-ligand (PD-L) 1 and PD-L2, transferred T cells failed to convert into T reg cells, and the mice quickly succumbed to inflammatory disease. Factors like TGF-β, IL-2, and Runx3 also help trigger and maintain T reg cells. PD-L1 augmented TGF-β signals, but also stimulated Foxp3 on its own. The authors also show that PD-L1 biased the differentiation of naive T cells toward a T reg cell fate by obstructing the Akt-mTOR signaling pathway required for effector T cell survival.

The PD-1 pathway keeps inflammation in check, the authors say. Inflammatory cytokines drive PD-1 expression, which in turn triggers T reg cells that dampen the inflammation. Manipulating this balance has been a long-standing therapeutic goal. Indeed, PD-1 and PD-L1 inhibitors are in clinical trials as anticancer agents. Francisco et al. suggest that PD-1 and PD-L1 agonists could also be used for the opposite effect—to sustain T reg cell function during organ transplantation or autoimmunity.