STING controls T cell memory fitness during infection through T cell intrinsic and IDO dependent mechanisms

Abstract

Stimulator of interferon genes (STING) signaling has been extensively studied in inflammatory diseases and cancer while its role in T cell responses to infection is unclear. Using Listeria monocytogenes strains engineered to induce different levels of c-di-AMP, we found that strong STING signals impaired T cell memory upon infection via increased Bim levels and apoptosis. Unexpectedly, reduction of TCR signal strength or T cell-STING expression decreased Bim expression, T cell apoptosis and recovered T cell memory. We found that TCR signal intensity coupled STING signal strength to the Unfolded Protein Response (UPR) and T cell survival. Under strong STING signaling, IDO inhibition also reduced apoptosis and led to a recovery of T cell memory in STING sufficient CD8 T cells. Thus, STING signaling regulates CD8 T cell memory fitness through both cell-intrinsic and extrinsic mechanisms. These studies provide insight into how IDO and STING therapies could improve long-term T cell protective immunity.