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. Significance StatementSTING signaling is an innate pathway that triggers host immunity against pathogens and cancer in response to cytosolic DNA. Additionally, STING signaling overactivation has been linked to autoimmunity. Yet, the interaction between antigenic and STING signaling and its impact in the development of protective immunity has remained unexplored. We found that strong levels of STING signaling impair CD8 T cell memory but only in response to high affinity TCR-pMHC interactions. Here, we provide evidence of how TCR signal strength controls STING signaling and IDO metabolism to regulate T cells survival as they mature to memory. These data have important implications for the design of STING and IDO combination immunotherapies